
==== Front
Cancer Immunol Immunother
Cancer Immunol Immunother
Cancer Immunology, Immunotherapy : CII
0340-7004
1432-0851
Springer Berlin Heidelberg Berlin/Heidelberg

39105817
3787
10.1007/s00262-024-03787-2
Research
Impact of the interval between neoadjuvant immunotherapy and surgery on prognosis in esophageal squamous cell carcinoma (ESCC): a real-world study
Yang Guozhen 123
Hong Yutong 13
Zhang Xiaomin 4
Zeng Chufeng 123
Tan Linyu 123
Zhang Xu xuz452866@gmail.com

123
1 https://ror.org/0400g8r85 grid.488530.2 0000 0004 1803 6191 Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
2 grid.488530.2 0000 0004 1803 6191 Guangdong Esophageal Cancer Institute, Guangzhou, China
3 grid.488530.2 0000 0004 1803 6191 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060 People’s Republic of China
4 https://ror.org/0064kty71 grid.12981.33 0000 0001 2360 039X School of Nursing, Sun Yat-Sen University, Guangzhou, China
6 8 2024
6 8 2024
10 2024
73 10 20224 4 2024
19 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

The time interval between neoadjuvant immunotherapy and surgery is 6 weeks for esophageal squamous cell carcinoma (ESCC), but whether delayed surgery affects prognosis remains unclear.

Methods

Clinical data of locally advanced ESCC who underwent neoadjuvant immunotherapy followed by esophagectomy from November 2019 to December 2022 were collected. The surgery outcomes and prognosis were compared between short-interval (time to surgery ≤ 6 weeks) and long-interval groups (time to surgery > 6 weeks).

Results

152 patients were enrolled totally, with a ratio of 91:61 between short-interval and long-interval groups. The rate of pathological complete response in the short-interval and long-interval groups were 34.1% and 24.6% (P = 0.257). Delayed surgery did not have a significantly impact on the number of lymph node dissections (P = 0.133), operative duration (P = 0.689), blood loss (P = 0.837), hospitalization duration (P = 0.293), chest drainage duration (P = 0.886) and postoperative complications (P > 0.050). The 3-year Overall survival (OS) rates were 85.10% in the short-interval group, and 82.07% in the long-interval group (P = 0.435). The 3-year disease-free survival (DFS) rates were 83.41% and 70.86% in the two groups (P = 0.037). Subgroup analysis revealed that patients with a favorable response to immunotherapy (tumor regression grade 0) exhibited inferior 3-year OS (long-interval vs. short-interval: 51.85% vs. 91.08%, P = 0.035) and DFS (long-interval vs. short-interval: 47.40% vs. 91.08%, P = 0.014) in the long-interval group.

Conclusions

Delayed surgery after neoadjuvant immunotherapy does not further improve pathological response; instead, it resulted in a poorer DFS. Especially for patients with a favorable response to immunotherapy, delayed surgery increases the risk of mortality and recurrence.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03787-2.

Keywords

Esophageal squamous cell carcinoma
Immunotherapy
Interval
Pathological complete response
Prognosis
the Science and Technology Program of Guangzhou, China202103000064 202103000064 202103000064 202103000064 202103000064 Yang Guozhen Zhang Xiaomin Zeng Chufeng Tan Linyu Zhang Xu the Science and Technology Project of Guangdong Esophageal Cancer Research InstituteQ202113 Hong Yutong issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Esophageal cancer ranks as the seventh most common malignant neoplasm worldwide and the sixth principal cause of cancer-induced mortality. According to the 2020 GLOBOCAN statistics [1], there are approximately 604,000 new cases of esophageal cancer worldwide each year, with around 544,000 new deaths. The incidence and mortality rates remain consistently elevated. China is identified as a high-incidence country for esophageal cancer, with esophageal squamous cell carcinoma (ESCC) constituting over 90% of cases. [2, 3]. The bulk of cases are typically identified at an locally advanced stage, due to the propensity for early lymph node metastasis.

In recent years, programmed death protein 1 (PD-1) antibodies plus neoadjuvant chemotherapy has been investigated in several clinical trials for locally advanced ESCC [4, 5]. This neoadjuvant regimen has demonstrated the potential to reduce the size of primary tumors, increase the success rate of surgical resection, achieve favorable rates of pathological complete response (pCR), and exhibit tolerable and manageable toxicity profiles. It offers promising prospects for widespread application in locally advanced ESCC. However, patient's condition after neoadjuvant treatment, local lesion and the systemic inflammatory response, can all impact surgical results. These factors may change over time, indicating that appropriate surgical timing is crucial for optimizing surgical outcomes. Current literature on the timing of surgery following neoadjuvant therapy shows inconsistent conclusions. Kim et al. [6] and Tessier et al. [7] reported that delayed surgery did not affect prognosis, whereas Qin et al. [8] observed that delayed surgery was associated with worse prognosis. Currently, most clinical trials performed surgery within 6 weeks after the end of neoadjuvant immunochemotherapy [9–11], which was based on the experience from traditional neoadjuvant chemoradiotherapy [12]. In traditional neoadjuvant chemoradiotherapy, surgery is typically scheduled within 4–6 weeks after radiotherapy to avoid exacerbating tissue fibrosis induced by radiation and increasing the surgical difficulty [13]. However, PD-1 inhibitor exert completely different mechanisms of action from radiation therapy, by obstructing the interaction between PD-1 and programmed death-ligand 1 (PD-L1), thus alleviating the suppression of T cells, and restoring their capacity to combat tumors. [14–16]. Additionally, the durable response of immunotherapy could promote tumor continue to shrink even after the drug is stopped for a period of time [17]. Therefore, it remains unclear whether delaying surgery in the context of immunotherapy would impact patient prognosis.

Therefore, we conducted a population-based, real-world, retrospective study, which enrolled patients with locally advanced ESCC who underwent neoadjuvant PD-1 inhibitor plus chemotherapy followed by surgery. The patient cohort was divided into short-interval group (time to surgery ≤ 6 weeks) and long-interval group (time to surgery > 6 weeks), to assess whether delayed surgery after immunotherapy affected surgical and pathological outcomes as well as long-term prognosis.

Methods

Patients selection

We retrospectively collected patients with ESCC who underwent neoadjuvant PD-1 inhibitor combined chemotherapy followed by surgery at the Department of Thoracic Surgery, Sun Yat-sen University Cancer Center from November 2019 to December 2022. Inclusion criteria were as follows: 1) age ranging from 18 to 80 years; 2) pathologically diagnosed with thoracic ESCC; 3) Clinical stage T1N1-3 or T2-4aN0-3 according to the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC), 8th edition; 4) administration of at least one cycle of PD-1 inhibitor combined chemotherapy prior to surgery; 5) availability of complete clinical, pathological, and follow-up data; 6) eastern cooperative oncology group (ECOG) performance status of 0–1. Exclusion criteria were: (1) adenocarcinoma, sarcoma, or other non-squamous cell carcinoma types; (2) received other neoadjuvant regimen before surgery, such as radiotherapy, targeted therapy; (3) clinical data missing.

Neoadjuvant regimen

In the overall cohort, the median number of neoadjuvant treatment cycles was 3 (range: 2–6). PD-1 inhibitors used in the study comprised camrelizumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and penpulimab. Chemotherapy regimens consisted of: (1) paclitaxel-based drugs plus platinum-based regimens, and (2) paclitaxel-based drugs plus fluoropyrimidine-based regimens. Detailed treatment protocols were provided in Supplementary Figure 1. Drug dosage and administration details were outlined in Supplementary Table 1.

Surgery procedure

Surgery was conducted after completing neoadjuvant therapy. The interval between neoadjuvant treatment and surgery was defined as the duration from the last cycle of treatment to the surgical procedure. Surgical approaches included traditional thoracotomy, McKeown or Ivor-Lewis minimally invasive esophagectomy (MIE), and robotic-assisted thoracoscopic/laparoscopic esophagectomy. Standard two-field lymph node dissection was conducted, with consideration of three-field lymph node dissection if preoperative cervical lymph node ultrasound indicated cervical lymph node metastasis. All surgical procedures were conducted by experienced thoracic surgeon.

Follow-up

The initial postoperative follow-up occurred at 3 months post-surgery, followed by subsequent visits every 3 months during the first two years, and thereafter at intervals of 6–12 months. Follow-up included contrast-enhanced computed tomography (CT) scans of the chest and abdomen, along with ultrasonography of the supraclavicular lymph nodes. If dysphagia or anastomotic leakage was suspected, electronic gastroscopy or endoscopic ultrasound (EUS) was performed. Positron emission tomography/computed tomography (PET-CT) was conducted if distant metastasis was suspected.

Study endpoint

The primary endpoints of the study comprised disease-free survival (DFS) and overall survival (OS), with secondary endpoints encompassing pathological complete response (pCR), objective response rate (ORR), primary tumor regression, lymph node regression, perioperative complications, and patterns of recurrence. DFS was delineated as the duration from surgery to the occurrence of disease recurrence, metastasis, or mortality, while OS was delineated as the duration from surgery to death from any cause. Evaluation of efficacy adhered to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1). Complete response (CR) denoted the disappearance of all target lesions. Partial response (PR) denoted a reduction in the sum of the longest diameters of all target lesions by 30% or more. Progressive disease (PD) denoted an increase in the sum of the longest diameters of all target lesions by at least 20%. Stable disease (SD) denoted a response between PR and PD. ORR was defined as the proportion of patients achieving CR or PR. Preoperative clinical TNM staging was conducted for all patients via imaging examination. Postoperative pathological TNM staging determined according to pathological findings. Staging adhered to the 8th edition of the UICC/AJCC TNM staging system.

Statistical analysis

Categorical variables were depicted as frequencies (%). Continuous variables following a normal distribution were expressed as mean ± standard deviation, whereas those not following a normal distribution are presented as median (IQR). The Chi-square test or Fisher’s exact test was employed for comparisons among categorical variables. The t-test or Wilcoxon test was utilized for comparisons among continuous variables. To mitigate the impact of clinical factors on endpoints, multivariable logistic regression models or multiple linear regression models were employed to adjust for age, sex, tumor location, differentiation, smoking history, alcohol consumption history, ECOG performance status, clinical T stage, clinical N stage, clinical TNM stage, cycles of neoadjuvant treatment, and the regimen of chemotherapy. The Kaplan–Meier method was utilized to estimate DFS and OS, with survival differences compared using the Log-rank test. Univariate and multivariate Cox regression models were applied to analyze the influence of clinical factors on prognosis. P value < 0.05 (both sides) was deemed statistically significant. All analyses were conducted using R version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline characteristics

From November 2019 to December 2022, 152 patients diagnosed with locally advanced ESCC underwent radical esophagectomy following neoadjuvant PD-1 inhibitor combined with chemotherapy at the Department of Thoracic Surgery of the Sun Yat-sen University Cancer Center. The median age of the included patients was 58 years (range: 41.0–78.0 years). All patients underwent clinical staging by chest enhanced CT scans and endoscopic examinations, with the majority being stage II-III (stage II: 36 cases, 23.7%; stage III: 90 cases, 59.2%). The median interval from the completion of the last neoadjuvant treatment to surgery was 5.71 weeks (range: 1.29–25.0 weeks). There were 91 cases in short-interval group (time to surgery ≤ 6 weeks), with a median time to surgery of 4.71 weeks (range: 1.29–6.0 weeks), and 61 cases in long-interval group (> 6 weeks), with a median time to surgery of 7.29 weeks (range: 6.14–25.0 weeks). The clinical baseline characteristics of the two groups were depicted in Table 1. Short-interval group and long-interval group were well-balanced and comparable in terms of sex (P = 0.264), age (P = 0.100), tumor location (P = 0.323), smoking history (P = 0.256), alcohol consumption history (P = 0.286), body mass index (BMI) (P = 0.927), ECOG performance status (P = 0.195), histological differentiation (P = 0.942), clinical T stage (P = 0.470), clinical N stage (P = 0.486), clinical TNM stage (P = 0.315), surgical approach (P = 0.615), and cycles of neoadjuvant treatment (P = 0.830).Table 1 Baseline characteristics of ESSS

Characteristics	Total (n = 152)	Short-interval group (n = 91)	Long-interval group (n = 61)	P value	
Sex	0.264	
 Male	128 (84.2%)	74 (81.3%)	54 (88.5%)		
 Female	24 (15.8%)	17 (18.7%)	7 (11.5%)		
Age (years old)	0.100	
 Mean	59.5	59.5	61.7		
 Median (Min, Max)	58.0 (41.0, 78.0)	58.0 (41.0, 78.0)	63 (31, 80)		
Tumor location	0.323	
 Upper thoracic	9 (5.9%)	4 (4.4%)	5 (8.2%)		
 Middle thoracic	94 (61.9%)	54 (59.3%)	40 (65.6%)		
 Lower thoracic	49 (32.2%)	33 (36.3%)	16 (26.2%)		
Smoking history	0.256	
 Yes	99 (65.1%)	56 (61.5%)	43 (70.5%)		
 No	53 (34.9%)	35 (38.5%)	18 (29.5%)		
Alcohol consumption history	0.286	
 Yes	57 (37.5%)	31 (34.1%)	26 (42.6%)		
 No	95 (62.5%)	60 (65.9%)	35 (85.4%)		
BMI (kg/m2)	0.927	
 ≦18.5	24 (15.8%)	14 (15.4%)	10 (16.4%)		
  > 18.5 and ≦23.9	95 (62.5%)	58 (63.7%)	37 (60.7%)		
  > 23.9	33 (21.7%)	19 (20.9%)	14 (22.9%)		
ECOG	0.195	
 0	99 (65.1%)	63 (69.2%)	36 (59.0%)		
 1	53 (34.9%)	28 (30.8%)	25 (41.0%)		
Differentiation	0.942	
 Well differentiated	7 (4.6%)	4 (4.4%)	3 (4.9%)		
 Moderately differentiated	108 (71.1%)	64 (70.3%)	44 (72.1%))		
 Poorly differentiated	37 (24.3%)	23 (25.3%)	14 (23.0%)		
Clinical stage T	0.470	
 T1	1 (0.6%)	1 (1.1%)	0 (0.0%)		
 T2	41 (27.0%)	26 (28.6%)	15 (24.6%)		
 T3	100 (65.8%)	60 (65.9%)	40 (65.6%)		
 T4	10 (6.6%)	4 (4.4%)	6 (9.8%)		
Clinical stage N	0.486	
 N0	17 (11.2%)	13 (14.3%)	4 (6.6%)		
 N1	63 (41.4%)	37 (40.6%)	26 (42.6%)		
 N2	53 (34.9%)	31 (34.1%)	22 (36.1%)		
 N3	19 (12.5%)	10 (11.0%)	9 (14.7%)		
Clinical stage TNM	0.315	
 I	1 (0.7%)	1 (1.1%)	0 (0.0%)		
 II	36 (23.7%)	25 (27.5%)	11 (18.0%)		
 III	90 (59.2%)	53 (58.2%)	37 (60.7%)		
 IV	25 (16.4%)	12 (13.2%)	13 (21.3%)		
Surgical approach	0.615	
 MIE	146 (96.1%)	88 (96.7%)	58 (95.1%)		
 Thoracotomy	6 (3.9%)	3 (3.3%)	3 (4.9%)		
Cycles of neoadjuvant treatment	0.830	
  ≤ 2	36 (23.7%)	21 (23.1%)	15 (24.6%)		
  > 2	116 (76.3%)	70 (76.9%)	46 (75.4%)		
Adjuvant treatment		
 Yes	9 (5.9%)	5 (5.5%)	4 (6.6%)	 > 0.999	
 No	143 (94.1%)	86 (94.5%)	57 (93.4%)		

Clinical effect and pathological outcomes

The clinical effect and pathological outcomes were shown in Table 2. After neoadjuvant PD-1 inhibitor combined with chemotherapy, 8.8% and 3.3% of patients in the short-interval and long-interval groups achieved CR (OR: 0.424, 95%CI: 0.097–1.851, P = 0.254), 65.9% and 73.8% of patients achieved PR (OR: 1.926, 95%CI: 0.844–4.396, P = 0.120), with no statistically significant differences between the two groups.Table 2 The clinical efficacy between short-interval group and long-interval group

	Short-interval group (n = 91)	Long-interval group (n = 61)	Before adjust	After adjust*	
			OR (95%CI)	P value	OR (95%CI)	P value	
CR	8 (8.8%)	2 (3.3%)	0.352 (0.073–1.531)	0.317	0.424 (0.097–1.851)	0.254	
PR	60 (65.9%)	45 (73.8%)	1.453 (0.717–2.975)	0.372	1.926 (0.844–4.396)	0.120	
SD	21 (23.1%)	13 (21.3%)	0.903 (0.415–1.955)	0.845	0.608 (0.252–1.464)	0.267	
PD	2 (2.2%)	1 (1.6%)	0.742 (0.050–6.500)	 > 0.999	0.118 (0.003–4.910)	0.261	
ORR	68 (74.7%)	47 (77.1%)	1.136 (0.547–2.346)	0.848	1.020 (0.442–2.356)	0.963	
T downstaging	63 (69.2%)	42 (68.9%)	0.983 (0.491–1.946)	1.000	0.993 (0.438–2.250)	0.986	
N downstaging	64 (70.3%)	45 (73.8%)	1.187 (0.570–2.468)	0.715	1.025 (0.404–2.603)	0.958	
TNM downstaging	65 (71.4%)	43 (70.5%)	0.956 (0.466–1.906)	1.000	0.980 (0.444–2.166)	0.961	
pCR	31 (34.1%)	15 (24.6%)	0.631 (0.299–1.297)	0.280	0.618 (0.269–1.421)	0.257	
*The multivariate logistic regression model adjusted age, sex, tumor location, differentiation, smoking history, alcohol consumption history, ECOG performance status, clinical T stage, clinical N stage, clinical TNM stage, cycles of neoadjuvant treatment and the regimen of chemotherapy

In terms of pathological outcomes, the proportions achieving pCR in the short-interval group and long-interval group were 34.1% and 24.6%, respectively. After adjustment, still no statistically significant disparity was observed between the two groups (OR: 0.618, 95%CI: 0.269–1.421, P = 0.257). Postoperative pathological results were compared with preoperative clinical staging. 69.2% and 68.9% of patients in the short-interval group and long-interval group experienced T downstaging (OR: 0.983, 95%CI: 0.491–1.946, P = 1.000), while 70.3% and 73.8% of patients experienced N downstaging (OR: 1.187, 95%CI: 0.570–2.468, P = 0.715). Regarding overall TNM staging, 71.4% and 70.5% of patients in the short-interval group and long-interval group, respectively, showed downstaging after neoadjuvant treatment, with no statistically significant difference between the two groups (OR: 0.956, 95%CI: 0.466–1.906, P = 1.000). Considering the impact of clinical factors and control for potential biases, adjustments were made for sex, age, tumor location, smoking status, drinking status, ECOG performance score, differentiation, clinical T stage, clinical N stage, clinical TNM stage, cycles of neoadjuvant treatment and regimen of chemotherapy. The results after adjustments still revealed that the interval between neoadjuvant immunotherapy and surgery had no significant impact on primary tumor and lymph node downstaging.

Adverse events of neoadjuvant treatment

The adverse effects of neoadjuvant treatment between short-interval and long-interval groups were displayed in Table 3. In short-interval group, 50.5% of patients experienced at least one adverse events, with the most common adverse events being anemia (39.6%), thyroid dysfunction (13.2%), increased alanine transaminase (11.0%), leukopenia (8.8%) and neutropenia (8.8%). In long-interval group, 59.0% of patients experienced at least one adverse events, with the most common being anemia (41.0%), leukopenia (16.4%), increased alanine transaminase (16.4%), neutropenia (13.1%) and thyroid dysfunction (9.8%). There was no statistically significant difference in the incidence of adverse events between the two groups.Table 3 The adverse effects between short-interval group and long-interval group

	Short-interval group (n = 91)	Long-interval group (n = 61)	Before adjust	After adjust*	
			OR (95%CI)	P value	OR (95%CI)	P value	
Total	46 (50.5%)	36 (59.0%)	1.409 (0.727–2.641)	0.320	1.158 (0.561–2.388)	0.692	
Leukopenia	8 (8.8%)	10 (16.4%)	2.034 (0.778–5.524)	0.201	1.578 (0.430–5.793)	0.492	
Neutropenia	8 (8.8%)	8 (13.1%)	1.566 (0.540–4.527)	0.428	1.167 (0.252–1.464)	0.819	
Anemia	36 (39.6%)	25 (41.0%)	1.061 (0.562–2.094)	0.868	1.228 (0.575–2.623)	0.596	
Increased alanine transaminase	10 (11.0%)	10 (16.4%)	1.588 (0.591–4.257)	0.340	2.339 (0.711–7.692)	0.162	
Thyroid dysfunction	12 (13.2%)	6 (9.8%)	0.718 (0.254–2.032)	0.615	0.848 (0.259–2.779)	0.785	

Surgery outcomes

As presented in Table 1 in Supplementary material 2, both groups of patients achieved R0 resection. There were no statistically significant differences between short-interval group and long-interval group in terms of the number of lymph nodes dissected (40.34 ± 16.77 vs. 44.51 ± 21.13, P = 0.133), positive lymph node counts (0.70 ± 1.82 vs. 0.74 ± 1.28, P = 0.887), operative time (325.13 ± 141.48 min vs. 340.30 ± 191.10 min, P = 0.689), blood loss (100 ml vs. 100 ml, P = 0.837), Intensive Care Unit (ICU) stay duration (2.49 ± 2.22 days vs. 2.52 ± 2.10 days, P = 0.961), hospitalization duration (14 days vs. 15 days, P = 0.293), and chest drainage duration (12.86 ± 8.58 days vs. 13.18 ± 9.59 days, P = 0.886). Regarding postoperative complications, both groups had similar rates of pneumonia (P = 0.386), respiratory failure (P = 0.430), pneumothorax (P = 0.144), anastomotic leak (P = 0.356), tracheal fistula (P = 1.000), chylothorax (P = 0.268), hemorrhage (P = 0.993) and kidney injury (P = 0.989).

Recurrence patterns

The recurrence patterns were summarized in Supplementary Table 2. The treatment failure patterns including local recurrence, distant metastasis or both. After adjustment for clinical factors, the short-interval group and long-interval group had 2.20% and 6.56% of patients experienced local recurrence, respectively (OR: 4.016, 95%CI: 0.469–34.414, P = 0.205), and 5.49% and 9.84% of patients experienced distant metastasis, respectively (OR: 1.686, 95CI: 0.343–8.292, P = 0.520). Additionally, 2.20% and 1.64% of patients experienced both local recurrence and distant metastasis simultaneously (OR: 0.403, 95%CI: 0.010–16.548, P = 0.632). The interval between neoadjuvant therapy and surgery showed no significant impact on the recurrence patterns.

Survival

The survival curves for both groups were depicted in Fig. 1. The median follow-up time was 24.1 months (range: 0.3–48.2 months) in the short-interval group and 19.5 months (range: 0.5–43.5 months) in the long-interval group. The median OS was not reached in either group (HR: 1.545, 95% CI: 0.518–4.608, P = 0.435). The 1-year, 2-year, and 3-year OS rates were 96.52%, 95.28%, and 85.10% in the short-interval group, and 96.58%, 87.55%, and 82.07% in the long-interval group, respectively. The median DFS also did not reach in both groups (HR: 2.414, 95% CI: 1.056–5.519, P = 0.037). The 1-year, 2-year, and 3-year DFS rates were 94.23%, 92.18%, and 83.41% in the short-interval group, and 88.02%, 75.92%, and 70.86% in the long-interval group, respectively.Fig. 1 Kaplan-Meier survival analysis. a Comparison of OS between short-interval group and long-interval group. b Comparison of DFS between short-interval group and long-interval group

To further clarify whether the time to surgery is a prognostic factor, the time to surgery and clinical factors were included in both univariate and multivariate cox regression models. The findings revealed that age (HR: 0.264, 95%CI: 0.090–0.778, P = 0.016) and ECOG performance status (HR: 5.616, 95%CI: 2.019–15.620, P < 0.001) were independent predictor of OS, while the time to surgery (HR: 2.082, 95%CI: 0.825–5.251, P = 0.120) was not. However, in terms of DFS, age (HR: 0.236, 95%CI: 0.079–0.707, P = 0.010), ECOG performance status (HR: 4.371, 95%CI: 1.664–11.483, P = 0.003) and the time to surgery (HR: 2.773, 95%CI: 1.074–7.162, P = 0.035) were all independent predictor of DFS. The univariate and multivariate cox regression analyses were depicted in Fig. 2.Fig. 2 Cox proportional hazards model for univariate and multivariate analysis. a The association between pretreatment characteristics and OS. b The association between pretreatment characteristics and DFS

According to the tumor regression grade (TRG) for subgroup analysis, in patients with a favorable response to immunotherapy (TRG 0), the short-interval group demonstrated 1-year, 2-year, and 3-year OS rates of 96.77%, 96.77%, and 91.08%, respectively, while the long-interval group showed 1-year, 2-year, and 3-year OS rates of 87.50%, 77.78%, and 51.85%, respectively. Delayed surgery significantly decreased the OS of TRG 0 cohort (HR: 6.372, 95% CI: 1.140–35.615, P = 0.035). In terms of DFS, the short-interval group exhibited 1-year, 2-year, and 3-year DFS rates of 96.77%, 96.77%, and 91.08%, respectively, while the long-interval group showed 1-year, 2-year, and 3-year DFS rates of 81.25%, 71.09%, and 47.40%, respectively. Delayed surgery similarly significantly reduced the DFS of TRG 0 cohort (HR: 8.031, 95%CI: 1.525–42.282, P = 0.014). For patients with slightly inferior pathological response (TRG 1–3), there were no statistically significant differences in OS (HR: 0.550, 95% CI: 0.107–2.840, P = 0.476) and DFS (HR: 1.466, 95% CI: 0.549–3.913, P = 0.445) between the short-interval and long-interval groups. The survival curves of different TRG were provided in Fig. 3.Fig. 3 Kaplan-Meier survival analysis according to the tumor regression grade (TRG). a Comparison of OS between short-interval group and long-interval group for patients with TGR 0 cohort. b Comparison of OS between short-interval group and long-interval group for patients with TRG 1-3 cohort. c Comparison of DFS between short-interval group and longinterval group for patients with TGR 0 cohort. d Comparison of DFS between short-interval group and long-interval group for patients with TRG 1-3 cohort

Discussion

Although the efficacy and safety of neoadjuvant PD-1 inhibitor combined with chemotherapy in locally advanced ESCC have been demonstrated in some clinical trials, the impact of the interval between immunotherapy and surgery on surgical outcomes and prognosis remains unclear. In this recent study, we compared outcomes between surgery within 6 weeks and surgery after 6 weeks following immunotherapy in the same real-world clinical practice setting. The findings revealed that delayed surgery had no significant impact on tumor downstaging, lymph node downstaging, pCR rate, and postoperative complications. However, delayed surgery was related to poorer prognosis.

Data on the optimal timing to surgery after neoadjuvant immunotherapy for ESCC are limited, but evidence on neoadjuvant chemoradiotherapy is abundant. Since the introduction of neoadjuvant chemoradiotherapy in the 1960s, it has been believed that surgery within 6 weeks is sufficient for tissue repair, resolution of tumor inflammatory response, and without causing tumor progression [18, 19]. The recommendation is to complete the surgical procedure within 4–6 weeks. Subsequent studies such as the NEOCRTEC5010 [20] and CROSS [21] trials also adopted a surgical regimen within 6 weeks after neoadjuvant treatment. Over the past few decades, a series of retrospective studies have evaluated the impact of timing to surgery after neoadjuvant chemoradiotherapy on histological response and prognosis. In studies by Lee et al. [22] and Azab et al. [23], the pCR rate increased with a prolonged interval between chemoradiotherapy and surgery, but long-term survival did not significantly improved. In a meta-analysis incorporating 10 cohort studies [24], it was found that delayed surgery did not further increase the pCR rate and OS, but rather increased the risk of anastomotic leakage. Klevebro et al. [25] similarly found no evidence to support extending the interval between chemoradiotherapy and surgery for esophageal cancer. Chiu et al. [26] reported that delayed surgery did not reduce surgical risk or increase the pCR rate, and survival was not improved either. The NeoRes II trial [27] is currently the only randomized controlled multi-center clinical trial comparing the standard time to surgery (4–6 weeks) with extended interval to surgery after neoadjuvant chemoradiotherapy for esophageal carcinoma, and the findings revealed that prolonging the surgical interval did not enhance pCR rate. Furthermore, There was a notable inclination towards poorer survival outcomes with an extended duration to surgery. These findings collectively advocate for prudence in deferring surgery following neoadjuvant chemoradiotherapy.

Compared to neoadjuvant chemoradiotherapy, immunotherapy has shown comparable efficacy in ESCC. Additionally, the tumor response patterns after immunotherapy are more diverse, with durable response patterns observed in many tumors [28]. This leads us to considered the necessity of delaying surgery in the context of immunotherapy. While clinical trials typically planed for surgery within 6 weeks after completion of immunotherapy, in real-world scenarios, surgery often occurred beyond this timeframe due to patient-related factors or the COVID-19 pandemic. In this study, we retrospectively reviewed information from patients with ESCC who underwent neoadjuvant immunotherapy combined with chemotherapy. The results revealed that delayed surgery failed to further promote primary lesion and lymph node downstaging, instead, the pCR rate was lower, although the difference was not statistically significant. This may be attributed to the relatively small sample size of the study cohort, but this trend is noteworthy, suggested that delaying surgery may entail the risk of further local lession progression.

Liang et al. found severe tissue edema and unclear tissue interspaces occurred after immunotherapy, which may increased surgical difficulty [29]. Some studies also reported that a longer waiting time after neoadjuvant treatment could lead to more severe tissue fibrosis [30]. In our short-interval and long-interval groups, there were no disparities observed between the groups concerning surgical timing or blood loss, suggested that delaying surgery did not increase surgical difficulty. Additionally, the long-interval group had numerically more lymph node dissections, which also indicated that the surgical quality of the long-interval group was at least equivalent to that of the short-interval group. Both groups also showed no differences in postoperative complications, hospitalization duration, ICU stay duration and chest drainage duration. In summary, the interval between immunotherapy and surgery did not significantly affect intraoperative procedures and postoperative recovery.

Improving prognosis is the fundamental challenge in cancer treatment. In an in vitro study involving 4T1.2 tumor-bearing mice receiving immunotherapy, prolonging the interval between immunotherapy and surgery resulted in increased mortality among surviving mice [31]. This finding underscored the importance of carefully considering the timing of surgery to achieve better oncological outcomes. Similarly, in the follow-up of our study, we found that delaying surgery did not confer any OS improved and instead led to a significant decrease in DFS. We speculated that during the delay in surgery, some lesions may continue to progress, leading to worse outcomes. Additionally, in long-interval group, the pCR rate was only 24.6%, while the pCR rate in short-interval group could reach 34.1%. pCR is a significant factor for better prognosis [32], which may also lead to poorer prognosis in long-interval group. Lastly, the main reasons for delaying surgery were poor physical condition after neoadjuvant therapy or infection with COVID-19, both of which were factors influencing prognosis [33–36].

Currently, some researchers suggested to defer surgery for patients with complete clinical response (CCR) after neoadjuvant therapy for ESCC [37, 38], similar to the watch-and-wait strategy used in rectal cancer [39], but this lacks evidence-based support. Our study results did not support this proposition. Subgroup analysis based on TRG revealed that delaying surgery in patients with excellent pathological regression (TRG 0) actually increased the risk of death and disease recurrence. This suggested that early surgery remains the optimal choice for patients who respond well to immunotherapy. Future randomized controlled trials with expanded sample sizes are warranted to further substantiate the rationale behind the watch-and-wait strategy.

To our knowledge, this study represents the most extensive investigation to date regarding the impact of the interval between immunotherapy and surgery on pathological outcomes and prognosis. Moreover, the study is grounded in real-world data, thus mitigating selection bias. Nevertheless, several limitations persist. Firstly, due to the relatively recent initiation of neoadjuvant immunotherapy research for esophageal squamous cell carcinoma, the sample size collected from a single center remains limited, which may impact the generalizability of our conclusions. In the future, it will be necessary to combine data from other medical centers to provide more comprehensive evidence. Secondly, the immunotherapeutic agents included in this study were all PD-1 antibodies, which have similar pharmacological actions and efficacy, resulting in minimal bias. However, there was significant variability in chemotherapy regimens, primarily divided into two categories: paclitaxel plus platinum and paclitaxel plus fluorouracil. This variability arises from differences in chemotherapy drug selection by different physicians when making treatment decisions. Although we adjusted for chemotherapy regimens in our analysis, there may still be some impact on the results. Thirdly, in this study, the number of neoadjuvant treatment cycles was also inconsistent. Most patients received three cycles of treatment, but a small number of patients exceeded three cycles. This inconsistency in treatment cycles may also influence the outcomes. Lastly, the follow-up period was relatively short, necessitating longer-term follow-up to validate the long-term prognosis.

Conclusion

Delayed surgery after neoadjuvant PD-1 inhibitor combined with chemotherapy does not further improve primary tumor and lymph node downstaging or increase pCR rates; instead, it resulted in a poorer DFS. Especially for patients with a favorable response to immunotherapy, delayed surgery increases the risk of mortality and recurrence. Therefore, we recommend surgery within 6 weeks after neoadjuvant immunotherapy as prudent.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 95 KB)

Supplementary file2 (DOCX 16 KB)

Acknowledgements

The authors would like to acknowledge all patients participating in the study.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Guozhen Yang and Yutong Hong. The first draft of the manuscript was written by Guozhen Yang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the Science and Technology Program of Guangzhou, China (202103000064), and the Science and Technology Project of Guangdong Esophageal Cancer Research Institute (Q202113).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Consent to publication

Informed consent was obtained from all individual participants included in the study.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Guozhen Yang and Yutong Hong have contributed equally to this work.
==== Refs
References

1. Sung H Ferlay J Siegel RL Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J] CA Cancer J Clin 2021 71 3 209 249 10.3322/caac.21660 33538338
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin 71(3):209–24933538338 10.3322/caac.21660
2. Abnet CC Arnold M Wei WQ Epidemiology of esophageal squamous cell carcinoma [J] Gastroenterology 2018 154 2 360 373 10.1053/j.gastro.2017.08.023 28823862
Abnet CC, Arnold M, Wei WQ (2018) Epidemiology of esophageal squamous cell carcinoma [J]. Gastroenterology 154(2):360–37328823862 10.1053/j.gastro.2017.08.023
3. Arnold M Soerjomataram I Ferlay J Global incidence of oesophageal cancer by histological subtype in 2012 [J] Gut 2015 64 3 381 387 10.1136/gutjnl-2014-308124 25320104
Arnold M, Soerjomataram I, Ferlay J et al (2015) Global incidence of oesophageal cancer by histological subtype in 2012 [J]. Gut 64(3):381–38725320104 10.1136/gutjnl-2014-308124
4. Yang W Xing X Yeung SJ Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma [J] J Immunother Cancer 2022 10 1 e003947 10.1136/jitc-2021-003497
Yang W, Xing X, Yeung SJ et al (2022) Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma [J]. J Immunother Cancer 10(1):e00394710.1136/jitc-2021-003497
5. Yan X Duan H Ni Y Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: a prospective, single-arm, phase II study (TD-NICE) [J] Int J Surg 2022 103 106680 10.1016/j.ijsu.2022.106680 35595021
Yan X, Duan H, Ni Y et al (2022) Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: a prospective, single-arm, phase II study (TD-NICE) [J]. Int J Surg 103:10668035595021 10.1016/j.ijsu.2022.106680
6. Kim JY Correa AM Vaporciyan AA Does the timing of esophagectomy after chemoradiation affect outcome? [J] Ann Thorac Surg 2012 93 1 207 213 10.1016/j.athoracsur.2011.05.021 21962263
Kim JY, Correa AM, Vaporciyan AA et al (2012) Does the timing of esophagectomy after chemoradiation affect outcome? [J]. Ann Thorac Surg 93(1):207–21321962263 10.1016/j.athoracsur.2011.05.021
7. Tessier W Gronnier C Messager M Does timing of surgical procedure after neoadjuvant chemoradiation affect outcomes in esophageal cancer? [J] Ann Thorac Surg 2014 97 4 1181 1189 10.1016/j.athoracsur.2013.12.026 24529482
Tessier W, Gronnier C, Messager M et al (2014) Does timing of surgical procedure after neoadjuvant chemoradiation affect outcomes in esophageal cancer? [J]. Ann Thorac Surg 97(4):1181–118924529482 10.1016/j.athoracsur.2013.12.026
8. Qin Q Xu H Liu J Does timing of esophagectomy following neoadjuvant chemoradiation affect outcomes? A meta-analysis [J] Int J Surg 2018 59 11 18 10.1016/j.ijsu.2018.09.013 30261331
Qin Q, Xu H, Liu J et al (2018) Does timing of esophagectomy following neoadjuvant chemoradiation affect outcomes? A meta-analysis [J]. Int J Surg 59:11–1830261331 10.1016/j.ijsu.2018.09.013
9. Liu J Yang Y Liu Z Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma [J] J Immunother Cancer 2022 10 3 e004291 10.1136/jitc-2021-004291 35338088
Liu J, Yang Y, Liu Z et al (2022) Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma [J]. J Immunother Cancer 10(3):e00429135338088 10.1136/jitc-2021-004291
10. Chen X Xu X Wang D Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): an open-label, single-arm, phase 2 trial [J] J Immunother Cancer 2023 11 2 e005830 10.1136/jitc-2022-005830 36759013
Chen X, Xu X, Wang D et al (2023) Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): an open-label, single-arm, phase 2 trial [J]. J Immunother Cancer 11(2):e00583036759013 10.1136/jitc-2022-005830
11. Yang G Su X Huang Y Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: a single-arm, phase II trial [J] J Transl Med 2023 21 1 411 10.1186/s12967-023-04273-6 37355621
Yang G, Su X, Huang Y et al (2023) Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: a single-arm, phase II trial [J]. J Transl Med 21(1):41137355621 10.1186/s12967-023-04273-6
12. Yang H Liu H Chen Y Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: The NEOCRTEC5010 randomized clinical trial [J] JAMA Surg 2021 156 8 721 729 10.1001/jamasurg.2021.2373 34160577
Yang H, Liu H, Chen Y et al (2021) Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: The NEOCRTEC5010 randomized clinical trial [J]. JAMA Surg 156(8):721–72934160577 10.1001/jamasurg.2021.2373
13. Han D Li B Zhao Q The key clinical questions of neoadjuvant chemoradiotherapy for resectable esophageal cancer-a review [J] Front Oncol 2022 12 890688 10.3389/fonc.2022.890688 35912182
Han D, Li B, Zhao Q et al (2022) The key clinical questions of neoadjuvant chemoradiotherapy for resectable esophageal cancer-a review [J]. Front Oncol 12:89068835912182 10.3389/fonc.2022.890688
14. Kuzume A Chi S Yamauchi N Immune-checkpoint blockade therapy in lymphoma [J] Int J Mol Sci 2020 21 15 5456 10.3390/ijms21155456 32751706
Kuzume A, Chi S, Yamauchi N et al (2020) Immune-checkpoint blockade therapy in lymphoma [J]. Int J Mol Sci 21(15):545632751706 10.3390/ijms21155456
15. Yin J Wu Y Yang X checkpoint inhibitor pneumonitis induced by anti-PD-1/PD-L1 therapy in non-small-cell lung cancer: occurrence and mechanism [J] Front Immunol 2022 13 830631 10.3389/fimmu.2022.830631 35464480
Yin J, Wu Y, Yang X et al (2022) checkpoint inhibitor pneumonitis induced by anti-PD-1/PD-L1 therapy in non-small-cell lung cancer: occurrence and mechanism [J]. Front Immunol 13:83063135464480 10.3389/fimmu.2022.830631
16. Tang Q Chen Y Li X The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers [J] Front Immunol 2022 13 964442 10.3389/fimmu.2022.964442 36177034
Tang Q, Chen Y, Li X et al (2022) The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers [J]. Front Immunol 13:96444236177034 10.3389/fimmu.2022.964442
17. Borcoman E Kanjanapan Y Champiat S Novel patterns of response under immunotherapy [J] Ann Oncol 2019 30 3 385 396 10.1093/annonc/mdz003 30657859
Borcoman E, Kanjanapan Y, Champiat S et al (2019) Novel patterns of response under immunotherapy [J]. Ann Oncol 30(3):385–39630657859 10.1093/annonc/mdz003
18. Cliffton EE Goodner JT Bronstein E Preoperative irradiation for cancer of the esophagus [J] Cancer 1960 13 37 45 10.1002/1097-0142(196001/02)13:1<37::AID-CNCR2820130108>3.0.CO;2-6 13810701
Cliffton EE, Goodner JT, Bronstein E (1960) Preoperative irradiation for cancer of the esophagus [J]. Cancer 13:37–4513810701 10.1002/1097-0142(196001/02)13:1<37::AID-CNCR2820130108>3.0.CO;2-6
19. Kakei H Arizumi N Okawa H Preoperative irradiation of cancer of the upper and mid-thoracic esophagus] [J Gan No Rinsho 1965 11 12 795 803 5894617
Kakei H, Arizumi N, Okawa H et al (1965) Preoperative irradiation of cancer of the upper and mid-thoracic esophagus] [J. Gan No Rinsho 11(12):795–8035894617
20. Yang H Liu H Chen Y 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] J Clin Oncol 2018 36 27 2796 2803 10.1200/JCO.2018.79.1483 30089078
Yang H, Liu H, Chen Y et al (2018) 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]. J Clin Oncol 36(27):2796–280330089078 10.1200/JCO.2018.79.1483
21. Shapiro J van Lanschot JJB Hulshof M Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial [J] Lancet Oncol 2015 16 9 1090 1098 10.1016/S1470-2045(15)00040-6 26254683
Shapiro J, van Lanschot JJB, Hulshof M et al (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial [J]. Lancet Oncol 16(9):1090–109826254683 10.1016/S1470-2045(15)00040-6
22. Lee A Wong AT Schwartz D Is there a benefit to prolonging the interval between neoadjuvant chemoradiation and esophagectomy in esophageal cancer? [J] Ann Thorac Surg 2016 102 2 433 438 10.1016/j.athoracsur.2016.02.058 27154156
Lee A, Wong AT, Schwartz D et al (2016) Is there a benefit to prolonging the interval between neoadjuvant chemoradiation and esophagectomy in esophageal cancer? [J]. Ann Thorac Surg 102(2):433–43827154156 10.1016/j.athoracsur.2016.02.058
23. Azab B Amundson JR Picado O Impact of chemoradiation-to-surgery interval on pathological complete response and short- and long-term overall survival in esophageal cancer patients [J] Ann Surg Oncol 2019 26 3 861 868 10.1245/s10434-018-6897-4 30311162
Azab B, Amundson JR, Picado O et al (2019) Impact of chemoradiation-to-surgery interval on pathological complete response and short- and long-term overall survival in esophageal cancer patients [J]. Ann Surg Oncol 26(3):861–86830311162 10.1245/s10434-018-6897-4
24. Tie H He F Shen J Prolonged interval between neoadjuvant chemoradiotherapy and esophagectomy does not benefit the outcome in esophageal cancer: a systematic review and meta-analysis [J] Dis Esophagus 2018 31 1 1 9 10.1093/dote/dox116 29087451
Tie H, He F, Shen J et al (2018) Prolonged interval between neoadjuvant chemoradiotherapy and esophagectomy does not benefit the outcome in esophageal cancer: a systematic review and meta-analysis [J]. Dis Esophagus 31(1):1–929087451 10.1093/dote/dox116
25. Klevebro F Nilsson K Lindblad M Association between time interval from neoadjuvant chemoradiotherapy to surgery and complete histological tumor response in esophageal and gastroesophageal junction cancer: a national cohort study Diseases of the Esophagus 2020 33 5 doz078 10.1093/dote/doz078 31676895
Klevebro F, Nilsson K, Lindblad M et al (2020) Association between time interval from neoadjuvant chemoradiotherapy to surgery and complete histological tumor response in esophageal and gastroesophageal junction cancer: a national cohort study. Diseases of the Esophagus 33(5):doz07831676895 10.1093/dote/doz078
26. Chiu CH Chao YK Chang HK Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? [J] Ann Surg Oncol 2013 20 13 4245 4251 10.1245/s10434-013-3139-7 23959050
Chiu CH, Chao YK, Chang HK et al (2013) Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? [J]. Ann Surg Oncol 20(13):4245–425123959050 10.1245/s10434-013-3139-7
27. Nilsson K Klevebro F Sunde B Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial [J] Ann Oncol 2023 34 11 1015 1024 10.1016/j.annonc.2023.08.010 37657554
Nilsson K, Klevebro F, Sunde B et al (2023) Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial [J]. Ann Oncol 34(11):1015–102437657554 10.1016/j.annonc.2023.08.010
28. Borcoman E Nandikolla A Long G Patterns of response and progression to immunotherapy [J] Am Soc Clin Oncol Educ Book 2018 38 169 178 10.1200/EDBK_200643 30231380
Borcoman E, Nandikolla A, Long G et al (2018) Patterns of response and progression to immunotherapy [J]. Am Soc Clin Oncol Educ Book 38:169–17830231380 10.1200/EDBK_200643
29. Liang H Yang C Gonzalez-Rivas D Sleeve lobectomy after neoadjuvant chemoimmunotherapy/chemotherapy for local advanced non-small cell lung cancer [J] Transl Lung Cancer Res 2021 10 1 143 155 10.21037/tlcr-20-778 33569300
Liang H, Yang C, Gonzalez-Rivas D et al (2021) Sleeve lobectomy after neoadjuvant chemoimmunotherapy/chemotherapy for local advanced non-small cell lung cancer [J]. Transl Lung Cancer Res 10(1):143–15533569300 10.21037/tlcr-20-778
30. Lefevre JH Mineur L Kotti S Effect of interval (7 or 11 weeks) between neoadjuvant Radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6) [J] J Clin Oncol 2016 34 31 3773 3780 10.1200/JCO.2016.67.6049 27432930
Lefevre JH, Mineur L, Kotti S et al (2016) Effect of interval (7 or 11 weeks) between neoadjuvant Radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6) [J]. J Clin Oncol 34(31):3773–378027432930 10.1200/JCO.2016.67.6049
31. Liu J O'Donnell JS Yan J Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome [J] Oncoimmunology 2019 8 5 e1581530 10.1080/2162402X.2019.1581530 31069141
Liu J, O’Donnell JS, Yan J et al (2019) Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome [J]. Oncoimmunology 8(5):e158153031069141 10.1080/2162402X.2019.1581530
32. Al-Kaabi A van der Post RS van der Werf LR Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: a population-based study [J] Acta Oncol 2021 60 4 497 504 10.1080/0284186X.2020.1870246 33491513
Al-Kaabi A, van der Post RS, van der Werf LR et al (2021) Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: a population-based study [J]. Acta Oncol 60(4):497–50433491513 10.1080/0284186X.2020.1870246
33. Shinall MC Arya JR Youk A Association of preoperative patient frailty and operative stress with postoperative mortality [J] JAMA Surg 2020 155 1 e194620 10.1001/jamasurg.2019.4620 31721994
Shinall MC, Arya JR, Youk A et al (2020) Association of preoperative patient frailty and operative stress with postoperative mortality [J]. JAMA Surg 155(1):e19462031721994 10.1001/jamasurg.2019.4620
34. Panayi AC Orkaby AR Sakthivel D Impact of frailty on outcomes in surgical patients: a systematic review and meta-analysis [J] Am J Surg 2019 218 2 393 400 10.1016/j.amjsurg.2018.11.020 30509455
Panayi AC, Orkaby AR, Sakthivel D et al (2019) Impact of frailty on outcomes in surgical patients: a systematic review and meta-analysis [J]. Am J Surg 218(2):393–40030509455 10.1016/j.amjsurg.2018.11.020
35. Liu C Zhao Y Okwan-Duodu D COVID-19 in cancer patients: risk, clinical features, and management [J] Cancer Biol Med 2020 17 3 519 527 10.20892/j.issn.2095-3941.2020.0289 32944387
Liu C, Zhao Y, Okwan-Duodu D et al (2020) COVID-19 in cancer patients: risk, clinical features, and management [J]. Cancer Biol Med 17(3):519–52732944387 10.20892/j.issn.2095-3941.2020.0289
36. Doglietto F Vezzoli M Gheza F Factors associated with surgical mortality and complications among patients with and without coronavirus disease 2019 (COVID-19) in Italy [J] JAMA Surg 2020 155 8 691 702 10.1001/jamasurg.2020.2713 32530453
Doglietto F, Vezzoli M, Gheza F et al (2020) Factors associated with surgical mortality and complications among patients with and without coronavirus disease 2019 (COVID-19) in Italy [J]. JAMA Surg 155(8):691–70232530453 10.1001/jamasurg.2020.2713
37. Castoro C Scarpa M Cagol M Complete clinical response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic oesophagus: is surgery always necessary? [J] J Gastrointest Surg 2013 17 8 1375 1381 10.1007/s11605-013-2269-3 23797888
Castoro C, Scarpa M, Cagol M et al (2013) Complete clinical response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic oesophagus: is surgery always necessary? [J]. J Gastrointest Surg 17(8):1375–138123797888 10.1007/s11605-013-2269-3
38. van der Wilk BJ Eyck BM Hofstetter WL Chemoradiotherapy followed by active surveillance versus standard esophagectomy for esophageal cancer: a systematic review and individual patient data meta-analysis [J] Ann Surg 2022 275 3 467 476 10.1097/SLA.0000000000004930 34191461
van der Wilk BJ, Eyck BM, Hofstetter WL et al (2022) Chemoradiotherapy followed by active surveillance versus standard esophagectomy for esophageal cancer: a systematic review and individual patient data meta-analysis [J]. Ann Surg 275(3):467–47634191461 10.1097/SLA.0000000000004930
39. Maas M Beets-Tan RG Lambregts DM Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer [J] J Clin Oncol 2011 29 35 4633 4640 10.1200/JCO.2011.37.7176 22067400
Maas M, Beets-Tan RG, Lambregts DM et al (2011) Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer [J]. J Clin Oncol 29(35):4633–464022067400 10.1200/JCO.2011.37.7176
