Impact of Timing on Post-Operative Outcomes in Esophagectomy for Squamous Cell Carcinoma: A Prospective Observational Study Comparing Surgery Within 8 Weeks vs. After 8 Weeks Post-Neoadjuvant Chemotherapy in a North Indian Tertiary Care Centre

doi:10.21203/rs.3.rs-4906258/v1

Purpose-: Neoadjuvant chemotherapy followed by esophagectomy is the usual approach to manage esophageal squamous cell carcinoma (ESCC). The optimal interval to operate after completion of Neoadjuvant Chemo-radiotherapy (NACRT) still remains controversial.

Methods:A prospective study was conducted to observe and compare post-operative complications and pathological outcomes in patients with squamous cell carcinoma of the esophagus who underwent NACRT followed by surgery within 8 weeks or after 8 weeks of NACRT completion. The pathological complete response was assessed using Mandard tumour regression grade. Morbidity and mortality were compared and were graded using Clavien-Dindo scale.

Results: The Study included 50 patients, 19 patients in within <8 week group and 31 in >8 week group study. Patients underwent thoracoscopy assisted esophagectomy with neoesophagus formation using gastric conduit. There was a significant difference between mortality between the two groups, with three mortalities in <8 week group and none in the other group (p=0.022). Postoperative complications and pathological outcomes did not have a statistically significant difference between the two groups.

Conclusion: The rate of post-operative complications and pathological response in ESCC cases do not appear to be impacted by the interval between NACRT and surgery; nevertheless, early surgery was associated with a higher risk of mortality.

Esophageal squamous cell carcinoma

conduit necrosis

chylothorax

pathological complete response

tumor regression grading.

Esophageal cancer (EC) is the 8th most common cancer worldwide and accounts for 3.2% of all new cases. Approximately 80% of cases of EC worldwide occur in less developed regions. In India, it is the fifth most common cancer type among males and the sixth most common cancer type among females [1]. In patients with EC, the majority of patients are symptomatic at the time of diagnosis. The most prevalent symptom at presentation is difficulty swallowing, which 74% of patients reported[2].

According to the guidelines of the National Comprehensive Cancer Network (NCCN), definitive chemoradiotherapy, neoadjuvant chemoradiotherapy followed by surgery (NACRT-OP), or esophagectomy alone are recommended for cT1b–4a, N0/+, and M0 patients [3]. Surgery after neoadjuvant chemoradiotherapy (NACRT) is the mainstay of treatment for locally advanced esophageal carcinoma because it results in a high rate of local disease control and patient survival [4]. NACT followed by surgery is commonly used as a standard therapeutic strategy for advanced esophageal squamous cell carcinoma (ESCC) in Japan according to the JCOG99075 trial [5]. In addition, neoadjuvant chemoradiotherapy (NCRT) followed by esophagectomy significantly improved survival in both the adenocarcinoma-dominant CROSS trial and the esophageal SCC-only NEOCRTEC50106 trial [6].

In recent years, tumor response to NACRT has also emerged as a potentially important predictor of local tumor control and patient survival. Therefore, NCRT is recommended for patients with both squamous cell carcinoma (SCC) and adenocarcinoma (AC) [7].Many recent large randomized trials of NCRT in patients with esophageal or esophagogastric junction cancer have shown significantly better disease-free survival without any significant increase in postoperative complications or in-hospital mortality [8, 9].

After NCRT, minimally invasive esophagectomy is an acceptable surgical therapy for advanced-stage esophageal malignancies, and there is evidence of decreased morbidity or mortality [10]. Routinely, esophagectomy is suggested to be performed within 3–8 weeks after NCRT [11-13]. However, various factors may push esophagectomy to progress well beyond 56 days after neoadjuvant treatment. Patients who underwent NACRT were diagnosed longer than patients who underwent surgery because of the former’s fragility and malnutrition, as well as the long-lasting side effects of the treatment. A long interval can be used to predict tumor regression, maximizing the long-term benefits of NACRT. However, the fibrosis that results from radiation exposure raises concerns that this could make surgery more challenging [14].

Only a few studies in the literature have evaluated the optimal timing of esophagectomy after NACRT, and the outcome of early or late esophagectomy after NACRT remains debatable. Furthermore, no study has been conducted on the Indian population. Thus, we opted to carry out this study to examine how the interval between NACRT and esophagectomy affects patient outcomes in terms of tumor response and perioperative complications.

This prospective study was conducted at the Postgraduate Institute of Medical Education and Research in Chandigarh, a tertiary care hospital in the Department of General Surgery. The study was approved by the Institutional Review Board (INT/IEC/2020/SPL-356). Patients were enrolled from January 2020 until January 2023, over a period of 3 years. In our study, 50 patients were enrolled, 19 in the ≤8-week group and 31 in the >8-week group.

Patients who were diagnosed with ESCC and consented to the study were enrolled. All the patients underwent upper gastrointestinal endoscopy and biopsy of the mass/ulcerative lesion. Contrast-enhanced computed tomography (CECT) of the chest and abdomen was performed to evaluate the disease stage. 18-Fluorodeoxyglucose positron emission tomography (18-FDG PET) was performed in patients with advanced ESCC for staging purposes. All disease stages deemed resectable, i.e., T1-T4a and N0/N+, were subjected to NACRT as per standard protocols, including carboplatin- and paclitaxel-based chemotherapy followed by radiotherapy or concurrent radiotherapy, in the Department of Radiation Oncology. After NACRT, a repeat CECT scan was conducted after at least six weeks. After assessing the resectability of the tumor, the patient was scheduled for surgery.

Surgery

Hybrid McKeown esophagectomy with the thorax performed using thoracoscopy was the chosen surgical management for all the patients. Two field lymphadenectomies and mediastinal and abdominal lymph node dissections were performed. A neoesophagus was formed in all patients who underwent surgery via the gastric conduit based on the right gastro-epiploic vessels passing through the posterior mediastinum. Cervico-esophageal anastomosis was performed using the modified collard technique. A neck drain and a hiatal drain were placed. Feeding jejunostomy, if not present, was performed for nutritional purposes.

Postoperative Care

Postoperatively, monitoring was performed as per routine procedures, and if any complication occurred, it was managed accordingly and graded according to the morbidity scale proposed by Clavien‒Dindo and colleagues [15]. The complications monitored included anastomotic leakage, conduit necrosis, chylothorax, pulmonary complications, including but not limited to effusion, RLN palsy, cardiac complications, and any other potential complications. All patients were discharged after they had recovered and started oral feeding, except for those who had an anastomotic leak or conduit necrosis and were discharged on FJ feed. These patients were subsequently followed up in the OPD until the establishment of oral feeding.

Histopathology

All resected specimens were evaluated histologically for tumor type, percentage of viable residual tumor compared with the tumor bed, extent of tumor, margin status and number of involved lymph nodes. After complete evaluation, tumor regression in the specimen was graded using Mandard’s tumor regression grading system.

Statistical analysis

The data were entered into a Microsoft Excel data sheet and analyzed using SPSS version 22 software. Categorical data are presented as frequencies and proportions. The chi-square test was used as a test of significance for qualitative data. Fischer’s exact test was used as a test of significance for qualitative data, which does not fulfill the criteria for the chi-square test (2x2 tables only). Continuous data are presented as the mean and standard deviation. The normality of the continuous data was tested by the Kolmogorov–Smirnov test and the Shapiro–Wilk test. Independent t tests were used to determine the significance of the differences in means between two quantitative variables. A p value <0.05 was considered to indicate statistical significance after all the rules of statistical tests were assumed.

A total of 50 patients with ESCC were enrolled in this study after providing informed consent. Patients were divided into two groups based on the interval between NACRT and surgery. The cutoff time was 8 weeks, and patients were divided into two groups: those who underwent surgery within 8 weeks (Group 1) and those who underwent surgery after 8 weeks (Group 2). Group 1 included 19 patients, and group 2 included 31 patients.

The demographic data, including age, sex, BMI, comorbidities and performance status, are summarized in Table 1. The mean age in group 1 was 51 years, whereas it was 56 years in group 2. The mean BMI was 20.3±4.12 in group 1 and 21.37±3.66 in group 2. Comorbidities were more prevalent in the > 8 weeks group, but the difference between the two groups was not found to be statistically significant. The performance status of all patients was measured, and the Eastern Cooperative Oncology Group (ECOG-1) score was 89.5% and 87.1% in Group 1 and Group 2, respectively.

The lower thoracic esophagus was more commonly involved in both groups, with 73% in group 1 and 64.5% in group 2. In the T stage, the maximum number of patients was found to be T3, with a 47% distribution in group 1 and a 54% distribution in group 2. The most common N stage was N1 in both groups. One patient in the early group had isolated adrenal metastasis; therefore, hybrid Mc-Kewon esophagectomy with adrenalectomy was performed on this patient (Table 2).

Intraoperative parameters were also monitored and compared between the two groups. The parameters noted were duration of surgery, intraoperative blood loss, need for intraoperative blood transfusion, and presence and density of adhesions on thoracoscopy, which were ranked using a 5-point Likert scale. The mean duration of surgery was 317 minutes in group 1 and 295 minutes in group 2 (Table 3). The mean blood loss was 235 ml in group 1 and 175 ml in group 2. Intraoperative blood transfusions were required for 21% of the patients in group 1 and 16% of the patients in group 2. Adhesions were graded by the operating surgeon on the basis of a 5-point Likert scale, with Grade 1 indicating no adhesions encountered and Grade 5 indicating very dense adhesions. Grade 1 restraint was more common in the late group (29%) than in the early group (15%) (Table 3). Grade 2, 4 and 5 adhesions were more commonly observed in group 1. However, the difference in adhesion between the two groups was not significant (p=0.390) (Table 3). The resection margin was R0 in all the patients.

The postoperative and pathological outcome data are summarized in Table 4. A pathological complete response was more common in the > 8 weeks group (group 2), in which 48% of the patients achieved a pathological complete response compared to 31% in the group 1 or ≤ 8 weeks group; however, the difference was not statistically significant (p=0.242). Mandard’s pathological grade was also calculated from the pathological report. Parenthood grades 4 and 5, which indicate a poor pathological response to neoadjuvant treatment, were more common in group 1 (31.6% and 10.5%, respectively). In terms of postoperative complications, four main parameters were monitored: anastomotic leakage, chylothorax, conduit necrosis and pulmonary complications; however, other complications, such as MI, atrial fibrillation and RLN palsy, were also encountered. The majority of patients developed basal atelectasis and mild pleural effusion. It was encountered in 36.8% of patients in group 1 and 19.4% of patients in group 2. However, most of these patients were managed with active chest physiotherapy, and 3 patients required pigtail insertion under the pleural cavity for effusion under local anesthesia. Only one patient in the early group experienced chylothorax requiring re-exploration and ligation of the thoracic duct. One patient in the early group developed conduit necrosis (Type II), which was managed with endoscopic vacuum therapy. Anastomotic leakage was observed in 21% of patients in group 1 and 12.9% of patients in group 2.

Three patients in the ≤ 8 weeks group had morphological abnormalities in the postoperative period, but no mortality was observed in the late group. The difference in mortality between the two groups was significant, with a p value of 0.022. One patient died of postoperative myocardial infarction on postoperative day one. Another patient died due to sepsis and multiple-organ dysfunction syndrome secondary to anastomotic leakage, and the third patient died due to severe pulmonary complications. The mean hospital stay was 17.32 ± 11.72 days in the early group and 19.61 ± 11.26 days in the late group.

In this study, we compared two groups of patients with ESCC. Group 1 included patients who underwent surgery within 8 weeks of completion of NCRT, and group 2 included patients who underwent surgery after 8 weeks. The two groups were compared in terms of demographic details, preoperative and intraoperative parameters and postoperative outcomes, including complications and pathological outcomes. Mortality during the postoperative period was the only significant difference between the two groups, with a higher incidence in the early group (p=0.22).

The timing of esophagectomy after the completion of NACRT plays an important role, as radiation-induced changes, recovery from chemotherapy and tumor response to NACRT affect the perioperative course and long-term survival. The main complications following esophagectomy are respiratory complications (atelectasis, pleural effusion, pneumothorax, pneumonia), wound infection, anastomotic leakage, anastomotic site stricture, conduit necrosis, vocal cord palsy, and chylothorax [16].

Numerous studies have demonstrated an increase in postoperative morbidity and mortality rates after a delay in surgery following NACRT [17-19]. In contrast, studies by Roul et al. and Xiao et al.showed no difference in postoperative complications between the two groups [20,21]. In our study, the tumor location was mostly in the lower thoracic esophagus in both groups, with no statistically significant difference, and T3 was the most common stage at presentation in both groups. This can be attributed to the fact that this stage corresponds to the development of significant dysphagia in patients with a disease; otherwise, there is no current evidence supporting the need for routine or high-risk group screening.

No significant difference was found in intraoperatively monitored parameters such as blood loss, duration of surgery or adhesions. However, a grade 3-5 incidence of adhesions per Likert scale was more common in group 1. This seems contrary to the generally accepted fact that adhesions become denser as the period after radiation increases. Theoretically, increasing the interval between NACRT and surgery may allow adequate time for patients to recover from adverse reactions to NACRT and may permit the tumor to continuously regress due to the prolonged effect of neoadjuvant treatment, thereby improving respectability [22]. However, a counterintuitive result might be explained by the viewpoint that waiting longer could make dissection more difficult and complicated due to increased radiation-related fibrosis. It is also possible that delaying surgery could allow for tumor regrowth, increasing the risk of recurrence [23].

A pathological complete response and Mandard grade 1 were more common in group 2 than in group 2, but the difference between the two groups was not statistically significant. Even in patients with incomplete response, higher T stages were more commonly found pathologically in group 1 despite an almost equitable distribution in pretreatment staging. In a meta-analysis performed by Qin Qin et al., a total of 13 studies involving 15,086 patients were analyzed. Overall, an interval longer than 7-8 weeks between the end of NACRT and surgery was significantly associated with an improved pCR rate [22]. Similarly, Xiao et al.also observed higher pCR rates with delay in surgery[21]. Like the NeoRes II trial, which is an RCT that included 223 patients with esophageal SCC who underwent esophagectomy after NCRT (117 within 6-8 weeks and 106 within 10-12 weeks) and showed no difference in postoperative complications between the two groups, our comparative data on postoperative complications and hospital stays were not statistically significant[24]. Pulmonary complications such as effusion and atelectasis were the most common events in both groups, but most of the patients did not require any additional therapeutic measures or other routine care, including physiotherapy. This can be attributed to thoracic dissection being performed to mobilize the esophagus and to lymph node retrieval as well as dissection in the upper abdomen to mobilize the stomach. Chylothorax and conduit necrosis were reported in one patient each in group 1 and group 2. An increased incidence of RLN palsy was found in the late group, likely due to difficult dissection secondary to radiation-related fibrosis.

Simon Roh et al. observed 348 EC patients with an increased risk of anastomotic leakage >35 days after surgery [25]. Wakita et al. conducted a study on 131 patients with EC and concluded that delaying esophagectomy may increase the rate of anastomotic leakage[26]. In our study, this delay did not seem to impact the rate of anastomotic leakage, as the difference was not significant, but leakage was more common in the early group. Moreover, the management of complications did not significantly differ between the two groups, as the difference in the Clavien‒Dindo grade was not statistically significant.

Postoperative mortality was significantly different (p=0.022): in the early group, 3 out of 19 patients died during the postoperative period, while no mortality occurred in the late group. This finding is contrary to the fact that demographic data, especially performance status, were not significantly different between the two groups. However, increased frailty and poor nutritional status due to more recent NACRT may be significant factors causing this difference, although this aspect requires additional detailed analysis.

Limitations of this study include the lack of long-term follow-up, lack of randomization, and limited sample size. This study still does not provide a clear answer for the optimum duration of surgery in patients with ESCC, but it is one of few initial studies performed for ESCC in the Indian population. More detailed studies, such as RCTs with longer follow-up periods, may provide better answers and fill the void in this area.

The interval between NACRT and surgery in patients with ESCC does not seem to affect the rate of postoperative complications or pathological response, although early surgery may contribute to a greater chance of mortality. Furthermore, additional multicentric randomized trials need to be conducted to determine the optimal duration of surgery after neoadjuvant therapy.

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Table 1: Demographic, comorbidity, and performance status comparisons between the two groups

		Group				p value
		<8 weeks (n = 19)		>8 weeks (n = 31)
		Count	%	Count	%
Mean Age		51.74±13.38		56.94±10.93		0.141
Age	<60	13	68.4%	17	54.8%	0.341
Age	>60	6	31.6%	14	45.2%	0.341
Gender	Female	8	42.1%	7	22.6%	0.144
Gender	Male	11	57.9%	24	77.4%	0.144
Mean BMI		20.31±4.12		21.37±3.66		0.348
BMI	<18.5	7	36.8%	7	22.6%	0.552
	18.5 to 24.9	9	47.4%	18	58.1%
	>25	3	15.8%	6	19.4%
DM	Yes	1	5.3%	4	12.9%	0.382
Respiratory comorbidity	Yes	0	0.0%	2	6.5%	0.258
Cardiac comorbidity	Yes	1	5.3%	3	9.7%	0.577
ECOG	0	1	5.3%	2	6.5%	0.857
	1	17	89.5%	27	87.1%
	2	1	5.3%	1	3.2%
	3	0	0.0%	1	3.2%

(BMI- Body mass index, DM- Diabetes mellitus, ECOG- Eastern Cooperative Oncology Group)

Table 2: Tumor distribution analysis of the two groups

		Group				p value
		≤8 weeks		>8 weeks
		Count	%	Count	%
Tumor location	Lower Thoracic	14	73.7%	20	64.5%	0.500
Tumor location	Mid Thoracic	5	26.3%	11	35.5%	0.500
T stage	T1	0	0.0%	1	3.2%	0.652
	T2	4	21.1%	6	19.4%
	T3	9	47.4%	17	54.8%
	T4a	5	26.3%	7	22.6%
	T4b	1	5.3%	0	0.0%
N stage	N0	5	26.3%	9	29.0%	0.232
	N1	12	63.2%	13	41.9%
	N2	2	10.5%	9	29.0%
M stage	M0	18	94.7%	31	100.0%	0.197
M stage	M1	1	5.3%	0	0.0%	0.197
Stage	I	0	0.0%	1	3.2%	0.767
	II	6	31.6%	12	38.7%
	III	7	36.8%	11	35.5%
	IVA	5	31.6%	7	22.6%
	IV B	1	5.3%	0	0.0%

Table 3: Intraoperative parameters

		Group				p value
		≤8 weeks		>8 weeks
		Count	%	Count	%
Mean duration of surgery		317.37 ±115.462		295.81 ±114.565		0.523
Mean Blood loss		235.00 ±129.672		175.67 ± 126.155		0.125
Blood loss(ml)	<150 ml	9	47.4%	21	67.7%	0.153
Blood loss(ml)	>150 ml	10	52.6%	10	32.3%	0.153
Need for blood transfusion	No	15	78.9%	26	83.9%	0.660
Need for blood transfusion	Yes	4	21.1%	5	16.1%	0.660
Adhesions	1	3	15.8%	9	29.0%	0.390
	2	8	42.1%	11	35.5%
	3	5	26.3%	6	19.4%
	4	0	0.0%	3	9.7%
	5	3	15.8%	2	6.5%
Resection margin	R0	19	100.0%	31	100.0%	-
Resection margin	R1	0	0.0%	0	0.0%	-

Table 4: Postoperative outcomes and analysis

		Group				p value
		≤8 weeks		>8 weeks
		Count	%	Count	%
Pathological complete response	Yes	6	31.6%	15	48.4%	0.242
Pathological complete response	No	13	68.4%	16	51.6%	0.242
Mandard's grading	1	7	36.8%	15	48.4%	0.845
	2	1	5.3%	3	9.7%
	3	3	15.8%	3	9.7%
	4	6	31.6%	8	25.8%
	5	2	10.5%	2	6.5%
Pathological T stage	T0	7	36.8%	15	48.4%	0.712
	T1	0	0.0%	1	3.2%
	T1b	2	10.5%	1	3.2%
	T2	3	15.8%	4	12.9%
	T3	7	36.8%	9	29.0%
	T4a	0	0.0%	1	3.2%
Pathological N stage	0.	18	94.7%	23	74.2%	0.154
	1.	1	5.3%	4	12.9%
	2.	0	0.0%	4	12.9%
Anastomosis leak	Yes	4	21.1%	4	12.9%	0.445
Chylothorax	Yes	1	5.3%	0	0.0%	0.197
Conduit necrosis	Yes	0	0.0%	1	3.2%	0.429
Pulmonary complication	Yes	7	36.8%	6	19.4%	0.171
Other Complications	No	17	89.5%	26	83.9%	0.364
	Atrial Fibrillation	0	0.0%	2	6.5%
	Myocardial Infarction	1	5.3%	0	0.0%
	RLN Palsy	1	5.3%	3	9.7%
Clavien‒Dindo	1.	10	52.6%	19	61.3%	0.282
	2.	2	10.5%	7	22.6%
	3A	2	10.5%	3	9.7%
	3B	1	5.3%	1	3.2%
	4a	1	5.3%	1	3.2%
	5.	3	15.8%	0	0.0%
Hospital stay (days)		17.32 ± 11.72		19.61 ± 11.26		0.494
Mortality	Yes	3	15.8%	0	0.0%	0.022

No competing interests reported.

Impact of Timing on Post-Operative Outcomes in Esophagectomy for Squamous Cell Carcinoma: A Prospective Observational Study Comparing Surgery Within 8 Weeks vs. After 8 Weeks Post-Neoadjuvant Chemotherapy in a North Indian Tertiary Care Centre

Status:

Version 1

Abstract

Background

Materials and Methods

Results

Discussion

Conclusion

References

Tables

Additional Declarations

Status:

Version 1