T S Piessen

Dabakuyo-Yonli

MD Wei Gilis Sheng

PharmD Emerline Assogba

MD, PhD ; Oumar Billa

MD, PhD Bernard Meunier

MD, PhD Johan Gagnière

MD, PhD Denis Collet

MD, PhD Xavier Benoît D'journo

MD, PhD Cécile Brigand

MD, PhD Guillaume Piessen

; Tienhan

PharmD Sandrine Dabakuyo-Yonli

Sandrine Tienhan

Thierry Perniceni

Nicolas Carrère

Jean-Yves Mabrut

Simon Msika

Frédérique Peschaud

Michel Prudhomme

PhD Fiona Ecarnot

Does baseline quality of life predict the occurrence of complications in resectable esophageal cancer?

Keywords: Health Related Quality of Life, esophagectomy, major complications, overall survival, prognostic factor

Main Text

Introduction

Esophageal cancer was the 8 th most common cancer diagnosed, and the 6 th leading cause of cancer-related death worldwide in 2020 [1]. Esophageal cancer is a highly fatal disease, with 5-year standardized net survival of 16% and 20% in men and women respectively in France [START_REF] Cariou | Survie des personnes atteintes de cancer en France métropolitaine 1989-2018[END_REF].

Esophagectomy remains the primary curative treatment option for patients with esophageal cancer. Five-year survival has increased to 40% among patients undergoing surgery compared to those without surgery [START_REF] Mariette | Oesophagogastric junction adenocarcinoma: which therapeutic approach?[END_REF]. Standard esophagectomy consists in an open surgical excision (laparotomy + right thoracotomy) for subcarinal thoracic esophageal cancer. It is associated with a significant risk of postoperative morbidity (30% to 50%) and mortality (2% to 10%) [START_REF] Hofstetter | Treatment outcomes of resected esophageal cancer[END_REF][START_REF] Karl | Factors affecting morbidity, mortality, and survival in patients undergoing Ivor Lewis esophagogastrostomy[END_REF][START_REF] Whooley | Analysis of reduced death and complication rates after esophageal resection[END_REF]. In recent years, minimally invasive approaches have been evaluated for esophagectomy, and have resulted in a decreased incidence of overall morbidity, pulmonary complications and a shorter length of hospital stay [START_REF] Mariette | Hybrid minimally invasive esophagectomy for esophageal cancer[END_REF][START_REF] Brierley | Laparoscopically assisted versus open esophagectomy for patients with esophageal cancer-the J o u r n a l P r e -p r o o f Randomised Esophagectomy: Minimally Invasive or Open (ROMIO) study: protocol for a randomised controlled trial (RCT)[END_REF][START_REF] Straatman | Minimally invasive versus open esophageal resection: three-year follow-up of the previously reported randomized controlled trial: the TIME trial[END_REF][START_REF] Pieter C Van Der Sluis | Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer: A Randomized Controlled Trial[END_REF].

The MIRO trial was a prospective, randomized, controlled, open-label, multicenter phase III study conducted in France to compare the morbidity, overall and disease-free survival, and health related quality of life (HRQOL) of patients undergoing open esophagectomy (open procedure) versus hybrid minimally invasive esophagectomy (hybrid procedure). The MIRO trial showed that the hybrid procedure resulted in a lower incidence of intraoperative and postoperative major complications, specifically pulmonary complications, compared to open esophagectomy, without compromising overall and disease-free survival or HRQOL over a period of 3 years [START_REF] Mariette | Hybrid minimally invasive esophagectomy for esophageal cancer[END_REF].

Previous studies have shown that baseline HRQOL can predict overall survival in patients with advanced cancer, such as glioblastoma, lung cancer, metastatic colorectal cancer, and J o u r n a l P r e -p r o o f esophageal cancer [START_REF] Mauer | The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study[END_REF][START_REF] Qi | Pre-treatment quality of life is an independent prognostic factor for overall survival in patients with advanced stage non-small cell lung cancer[END_REF][START_REF] Cramarossa | Predictive factors for overall quality of life in patients with advanced cancer[END_REF][START_REF] Lee | EORTC QLQ-C15-PAL quality of life score as a prognostic indicator of survival in patients with far advanced cancer[END_REF][START_REF] Diouf | Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study[END_REF]. However, data are lacking regarding the impact of baseline HRQOL on the occurrence of complications in patients with resectable esophageal cancer.

Therefore, we used the data from MIRO trial to assess the prognostic value of baseline HRQOL on the occurrence of major complications (MC) at 30 days after surgery in patients with resectable esophageal cancer. The secondary aims were to assess the prognostic value of baseline HRQOL on major pulmonary complications (MPC) at 30 days, and on 1-year overall survival (OS).

Methods

Study design and population

This study used data from MIRO. Briefly, the MIRO trial was a prospective, multicenter, open label, randomized, controlled phase III trial comparing the hybrid procedure to the open procedure in patients with resectable esophageal cancer. The patients were randomized from October 2009 through April 2012 in France, then followed up for 3 years after esophagectomy. MIRO inclusion criteria were patients aged 18-75 years with WHO performance status 0 to 2; diagnosed with squamous cell carcinoma (SCC) or adenocarcinoma of the middle or lower third of the esophagus with clinical stage I, II or III (T1, T2, T3; N0 or N1; M0), with the tumor judged as resectable pre-operation; with or without neoadjuvant therapy.

In the MIRO trial, patients were randomized intraoperatively after a laparoscopic exploration of the abdominal cavity to confirm the absence of contraindications to curative surgery (hepatic cirrhosis, hepatic or peritoneal metastasis, or non-resectable tumor extension), in a 1:1 ratio to either the open procedure (with open gastric mobilization and thoracotomy) or the hybrid procedure (laparoscopic gastric mobilization and open thoracotomy). All patients were followed up to 30 days after surgery and every 6 months for 3 years postoperatively. The design and the results of the MIRO trial have been previously published elsewhere [START_REF] Mariette | Hybrid minimally invasive esophagectomy for esophageal cancer[END_REF][16][START_REF] Briez | Open versus laparoscopically assisted esophagectomy for cancer: a multicentre randomised controlled phase III trial -the MIRO trial[END_REF].

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The present study included all patients who were randomized in the MIRO trial. Data on HRQOL, complications, and OS were collected.

Endpoints

The primary endpoint for this study was major complications during surgery or within 30(±3) days after surgery. A major intraoperative and/or postoperative complication was defined as a surgical or medical complication classed as grade II or higher on the five-grade Clavien-Dindo classification (including grade 1, 2a, 2b, 3 and grade 4, higher grades indicate more lifethreatening complications) [START_REF] Clavien | Severity Grading of Surgical Complications[END_REF]. The secondary endpoints were major pulmonary complications during surgery or within 30(±3) days after surgery, and 1-year overall survival.

Study Instruments

Baseline HRQOL was measured within 30 days before resection using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30, Version 3.0) and the esophageal cancer module-18 (EORTC QLQ-OES18).

EORTC QLQ-C30 is a 30-item questionnaire including five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom and six single item scales (fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties), and a global health status item. The QLQ-OES18 module includes 10 symptom scales and is used among patients with esophageal cancer undergoing any single treatment, or combination of treatments including: esophagectomy, chemo-radiation, endoscopic palliation, or palliative chemotherapy and/or radiotherapy [START_REF] Blazeby | Clinical and Psychometric Validation of an EORTC Questionnaire Module, the EORTC QLQ-OES18, to Assess Quality of Life in Patients with Esophageal Cancer[END_REF]. The score ranges from 0 to 100; high scores on functional scales (like role functioning) represent a high/ healthy level of functioning, J o u r n a l P r e -p r o o f whereas high scores on symptom scales (like fatigue, pain, or insomnia) represent a high level of symptomatology/ problems.

Statistical Analysis

Sociodemographic and clinical characteristics of patients at inclusion are described in the whole sample, as well as baseline HRQOL scores for each scale. Age (in years), body mass index (BMI, in kg/m 2 ), and baseline HRQOL scores are described as mean ± standard deviation (SD). Sex, WHO status, clinical tumor stage, presence of nodes on clinical examination, histological tumor type, tumor location, American Society of Anesthesiologists (ASA) score and type of neoadjuvant therapy are described as number and percentage. Survival curves were plotted using the Kaplan Meier Method.

Considering that among patients who reported "a small" change in HRQOL for better or for worse, the average change in scores was 5-10 points on the EORTC QLQ-C30 scales, we divided the initial scores of EORTC QLQ-C30 and EORTC QLQ-OES18 by ten, then used the quotient thus obtained for the assessment of prognostic value [START_REF] Osoba | Interpreting the significance of changes in health-related quality of life scores[END_REF]. This methodology is used to obtain a minimum clinically important difference [START_REF] Gourgou-Bourgade | Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial[END_REF].

Univariable and multivariable Cox models were used to assess the prognostic value of the baseline HRQOL score on the occurrence of MC, MPC and on 1-year OS. Univariable analysis was performed on each dimension of baseline EORTC QLQ-C30 and EORTC QLQ-OES18, and on the baseline demographic and clinical characteristics. The significance threshold was set at 0.05 for HRQOL and at 0.20 for the baseline demographic and clinical characteristics in univariable analysis. We used Spearman's correlation coefficient and the chi square or Fisher's exact test to test candidate variable independence. Next, we conducted a separate multivariable analysis for each dimension of the EORTC QLQ-C30 and QLQ-OES18 that was significant by univariable analysis. Analyses were adjusted for baseline demographic and clinical J o u r n a l P r e -p r o o f characteristics that were associated with the occurrence of MC or MPC at 30 days, or with 1year OS with a p-value <0.20 in univariable analysis. Multivariable analyses were systematically adjusted for age, ASA score, TNM stage and neoadjuvant therapy for the assessment of complications.

Final multivariable models were chosen based on clinical considerations and Harrell's C index.

Results are presented as Hazard Ratios (HR) and 95% confidence interval. The significance threshold was set at 0.05 for multivariable analyses. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Results

Baseline patient characteristics

In total, 207 patients were included in this study. The mean age was 60.37 (SD=8.81) years and 84.54% of patients were male. Forty one percent of patients were diagnosed with squamous cell carcinoma and 59% with adenocarcinoma. Two hundred and five patients underwent esophagectomy: 103 had an open procedure and 102 had a hybrid procedure; two patients were randomized but did not undergo surgery. The details of the baseline clinical characteristics are shown in Table 1.

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Overall, baseline HRQOL scores were good. The best functional score was the physical J o u r n a l P r e -p r o o f 2.76 (SD=9.22). "Global health status", with a mean of 69.49 (SD=19.66), was the worst functioning score, and dysphagia 76.6 (SD=27.28) was the highest symptomatic score (Table 2).

Primary and secondary endpoints

Among the 207 patients, 99 (47.83%) had one or more major complications 30 days after the esophagectomy, and more than 70% of complications occurred during the first week after surgery (Figure 1). Forty-nine of the 99 cases of major complications were pulmonary complications. At 1-year post surgery, 31 patients (14.98%) had died.

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Assessment of prognostic value

HRQOL and complications

In univariable analysis, role functioning (p=0.0425) and fatigue (p=0.033) on the QLQ-C30, and pain (p=0.038) on the QLQ-OES18 were significantly associated with the occurrence of MC. For MPC, only the fatigue (P=0.0424) and pain (p=0.0023) dimensions of the QLQ-C30 were statistically significant (Table 2).

The same dimensions were found to be associated with MC and MPC by multivariate analysis after adjusting for type of surgery, tumor histology, age, ASA score, and TNM classification (T and N), for both MC and MPC.

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Multivariable analyses also showed that, compared with the hybrid procedure, patients who underwent an open procedure had a significantly higher risk of both MC and MPC. In the model with fatigue, the HR for the occurrence of MC was 2.48 (95% CI 1.57 -3.92, p<0.001).

In the model with role functioning and OES18-pain, the HRs for MC were respectively 2.30 and 2.14 (p<0.001 for both). For risk of MPC, type of surgery showed a similar impact. Patients diagnosed with esophageal adenocarcinoma were at significantly lower risk of MC or MPC after surgery compared to patients with SCC. No difference was found for age, ASA score and TNM stage (Table 3).

HRQOL and 1-year postoperative OS

By univariable analyses, role functioning, nausea and vomiting, pain, dyspnoea, insomnia, and constipation on the QLQ-C30, and dysphagia, eating, and dry mouth on the QLQ-OES18 were the dimensions of HRQOL that were significantly associated with 1-year OS (Table 2).

By multivariable analysis, pain (HR=1.23; 95% CI [1.02-1.50]; p=0.035) and insomnia (HR=1.16; 95% CI [1.01-1.32]; P=0.031) on the QLQ-C30 were significant after adjustment for age, occurrence of major complications and pN stage. Patients with higher pain or insomnia scores (per 10-point increase) were at significantly higher risk of death at 1 year after surgery.

We also found pN stage to be a significant prognostic factor, whereby patients with more advanced pN stage (mainly for N2) had a higher risk of death at 1 year after surgery compared to patients with N0 stage. In the model with insomnia, node stage N2 was associated with a hazard ratio of 10.51 (95% CI 2.30-47.90, p=0.002) for 1-year death compared to node stage N0. The occurrence of major complications was significantly associated with an increased risk of death in both models (p=0.008 in the model with pain, and p=0.015 in the model with insomnia). Age over 60 years was a significant prognostic factor for death only in the model with the pain dimension, but not in the model with insomnia (Table 4).

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Discussion

In this study, we found that the initial HRQOL score (specifically, role functioning, fatigue and pain scales), surgical approach and histological type of esophageal cancer were significant predictors of the occurrence of MC and MPC. The results also showed that the baseline HRQOL score (specifically pain and insomnia) were predictors of 1-year overall survival after surgery.

In our study, every 10-point increase in the baseline role functioning score was associated with a 14% reduction in the risk of MC. Conversely, every 10-point increase in fatigue or OES18pain symptoms at baseline was associated with an 18% increase in the risk of MC. Similarly, every 10-point increase in pain or fatigue symptom scores was associated with a higher risk (20-24%) of MPC.

After esophagectomy for cancer, postoperative complications can directly affect long term oncological outcomes and HRQOL [START_REF] Nuytens | Five-Year Survival Outcomes of Hybrid Minimally Invasive Esophagectomy in Esophageal Cancer Results of the MIRO Randomized Clinical Trial[END_REF]. Patients' HRQOL could be influenced between 6 months and 3 years after surgery, and even after 10 years, patients still experience reduced J o u r n a l P r e -p r o o f HRQOL with persisting symptoms [START_REF] Djärv | Long-term health-related quality of life following surgery for esophageal cancer[END_REF][START_REF] Anna R Schandl | Health-related quality of life 10 years after esophageal cancer surgery[END_REF]. Postoperative complications after esophagectomy mainly include in the short-term pulmonary and cardiac complications, anastomotic leakage, chylothorax, and delayed gastric emptying, which mostly occurred during the first week after surgery [START_REF] Mariette | Hybrid minimally invasive esophagectomy for esophageal cancer[END_REF]. In the long-term, anastomotic stenosis and reflux oesophagitis can occur and potentially impair patients' HRQOL. Postoperative anastomotic leakage is one of the most important complications leading to death [START_REF] Xu | The treatments and postoperative complications of esophageal cancer: a review[END_REF]. The higher the incidence of postoperative pulmonary complications, the greater the harm. Reported risk factors for pulmonary complications include patients' smoking history, forced expiratory volume (FEV), chronic obstructive pulmonary disease (COPD), age, obesity, and lung diseases, while lymph node dissection status and preoperative serum albumin levels are risk factors for anastomotic leakage [START_REF] Shiozaki | Risk factors for postoperative respiratory complications following esophageal cancer resection[END_REF][START_REF] Ohi | Risk factors and measures of pulmonary complications after thoracoscopic esophagectomy for esophageal cancer[END_REF][START_REF] Aoyama | Risk factors for postoperative anastomosis leak after esophagectomy for esophageal cancer[END_REF]. In the present randomized, controlled study, strict inclusion/ exclusion criteria were applied, and a standardized perioperative pathway was proposed for all patients, including alcohol and smoking cessation for at least 1 month prior to surgery, oral immuno-nutrition and enteral nutritional assistance, intraoperative respiratory and cardiovascular monitoring and an algorithm of treatment for post-operative complications. Together, these contributed to minimizing differences between patients, leading to more convincing results. We focused our analysis on MC, including MPC, and found that nearly 50% of MC are pulmonary complications. In addition to the type of surgical approach and tumor histology, the initial HRQOL score (role functioning, fatigue and pain) could also play a role in the occurrence of complications. When performing preoperative assessment, in addition to routine tumor and clinical examinations, special attention should be paid to patients' HRQOL, such as pain and fatigue.

In our study, patients with higher baseline scores on the pain or insomnia dimensions were observed to be at greater risk (23% and 16% respectively) of death at one year after surgery.

Pain is a common symptom among patients with cancer, and adequate pain assessment and J o u r n a l P r e -p r o o f management are thus critical to improve the quality of life and health outcomes in this population [START_REF] Bethann | Optimal Pain Management for Patients with Cancer in the Modern Era[END_REF]. In our analysis, lymph node status was shown to be an important risk factor for death at 1 year, whereby patients with more advanced N stage (N2), had an approximately 10-fold increase in the risk of death. Furthermore, patients who experienced a MC had around a 3-fold increase in the risk of death at 1 year compared to patients who suffered no complication. In the multivariable model on the pain dimension, older age (> 60 years) was associated with a higher risk of death at 1 year. Previous studies have identified age, pathological T stage, clinical lymph node involvement and treatment modality (surgery versus definitive chemoradiotherapy) as predictive factors of death in esophageal cancer [START_REF] Zhang | Short-term postoperative complications and prognostic factors in patients with adenocarcinoma of the esophagogastric junction[END_REF][START_REF] Chen | Survival benefit of surgery to patients with esophageal squamous cell carcinoma[END_REF]. The study by Tamagawa et al showed that the development of postoperative pneumonia was a risk factor for decreased 5-year OS in patients who underwent curative surgery for esophageal cancer [START_REF] Tamagawa | esophageal cancer? Highlights Quality of life predicts the postoperative complications in esophageal cancer patients. Baseline role functioning had a protective effect against complications. Fatigue and pain were the risk factors of postoperative complications. Squamous cell pathology, pain and insomnia were risk factors for 1-year OS[END_REF]. In our analysis, age was a risk factor for 1-year overall survival in certain conditions. In clinical practice, management and treatment of MC, especially for older patients, is of paramount importance.

In a previous study assessing baseline HRQOL to predict OS in patients with advanced cancer, the dimensions such as global health status, physical functioning, fatigue, nausea, appetite loss and constipation were prognostic indicators of OS [START_REF] Cramarossa | Predictive factors for overall quality of life in patients with advanced cancer[END_REF][START_REF] Lee | EORTC QLQ-C15-PAL quality of life score as a prognostic indicator of survival in patients with far advanced cancer[END_REF][START_REF] Diouf | Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study[END_REF]. In the present study, we included patients with clinical tumor stage I, II or III. Generally, patients' baseline HRQOL scores were good in our study; and their health status were better than patients with advanced cancer. Nevertheless, our results also provide evidence that there is a need to be mindful of patients' overall syndromes, such as complaining of pain and insomnia, to ensure longer survival for patients undergoing esophagectomy.

Our study findings are in line with the previous MIRO and TIME studies [START_REF] Mariette | Hybrid minimally invasive esophagectomy for esophageal cancer[END_REF][START_REF] Straatman | Minimally invasive versus open esophageal resection: three-year follow-up of the previously reported randomized controlled trial: the TIME trial[END_REF], which showed that the hybrid procedure resulted in a lower incidence of MC or MPC compared to open esophagectomy.

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Conclusion

In conclusion, the role functioning, fatigue and pain were independent prognostic factors of complications in patients with resectable esophageal cancer treated with surgery. Role functioning had a protective effect against MC, while fatigue and pain were associated with an increased risk of the occurrence of MC or MPC. Regarding 1-year OS after surgery, pain and insomnia were prognostic risk factors for death; patients with squamous cell pathology, older age, and more advanced lymph node status were indicators of poor prognosis of OS. To patients with these presences, special attention should be paid, and it might possibly change the management plan towards other forms of treatment.

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Figure 1 .

 1 Figure 1. Kaplan Meier curve showing major complication-free survival.

Table 1 .

 1 Patients' baseline demographic and clinical characteristics (n=207):

	Characteristic		N	Percentage (%)
	Gender
		Male	175	84.54
		Female	32	15.46
	Age, years	Mean (SD)	207	60.37 (8.81)
		≤ 60	96	46.38
		> 60	111	53.62
	WHO performance status score
		0	120	57.97
		1	79	38.16
		2	8	3.86
	BMI, kg/m 2	Mean (SD)	25.31 (3.93)
	ASA risk score
		1	59	28.50
		2	119	57.49
		3	29	14.01
	Dysphagia score, Atkinson
		Able to eat a normal diet	104	50.24
		Able to eat some solid food	68	32.85
		Able to eat some semi solids only	22	10.63
		Liquid feed possible	11	5.31
		Complete dysphagia	2	0.97
	TNM Classification
	T T0	4	1.93
		T1	33	15.94
		T2	63	30.43
		T3+T4	98	47.34
		Missing data	9	4.35
	N N0	89	43.00
		N1	102	49.27
		N2	8	3.86
		Missing data	8	3.86
	Location of tumor in esophagus
		Upper third	1	0.48
		Middle third	63	30.43
		Lower third	143	69.08
	Tumor histology
		Squamous cell carcinoma	84	40.58
		Adenocarcinoma	123	59.42
	Neoadjuvant therapy
		Chemotherapy only	86	41.54
		Chemo-radiotherapy	66	31.88
		None	55	26.57
	Surgery type
		Hybrid procedure	102	49.28
		Open procedure	103	49.75
		None	2	0.97
	Abbreviations: SD, standard deviation; WHO, World Health Organization; BMI, body mass index; ASA,
	American Society of Anesthesiologists.

Table 2 .

 2 Baseline HRQOL score and the relation between baseline HRQOL scores and major complications, major pulmonary complications, and 1-year overall survival by univariable analysis:

	Dimensions	Baseline HRQOL	P-value from univariable analysis
		Mean (SD)	MC	MPC	1-year OS
	QLQ-C30 Questionnaire
	Global Health Status	69.49 (19.66)	0.1139	0.6277	0.1030
	Physical Functioning	91.82 (12.17)	0.1298	0.961	0.2113
	Role Functioning	88.41 (19.26)	0.0425	0.5958	0.0387
	Emotional Functioning	74.34 (22.65)	0.7510	0.9791	0.9679
	Cognitive Functioning	91.08 (14.51)	0.4197	0.9473	0.2606
	Social Functioning	87.54 (22.00)	0.6634	0.5053	0.2469
	Fatigue	23.88 (19.91)	0.0330	0.0424	0.3824
	Nausea and Vomiting	11.68 (22.88)	0.1146	0.4850	0.0007
	Pain	11.53 (17.46)	0.0517	0.0023	0.0486
	Dyspnoea	11.11 (19.58)	0.5706	0.5709	0.0107
	Insomnia	21.94 (26.80)	0.0840	0.9149	0.0063
	Appetite Loss	19.93 (30.41)	0.3405	0.9557	0.1173
	Constipation	20.54 (30.30)	0.5224	0.5970	0.0147
	Diarrhoea	10.32 (20.50)	0.9892	0.9756	0.7006
	Financial Difficulties	8.84 (21.38)	0.0690	0.1531	0.8756
	QLQ OES-18 Questionnaire
	Dysphagia	76.60 (27.28)	0.3887	0.7703	0.0091
	Eating	19.49 (23.50)	0.4001	0.7678	0.0241
	Reflux	18.28 (24.90)	0.6103	0.4365	0.2456
	Pain	11.34 (15.26)	0.0380	0.0557	0.2437
	Trouble Swallowing Saliva	8.12 (24.00)	0.6088	0.3821	0.9626
	Choked when swallowing	7.81 (17.47)	0.5403	0.7865	0.3961
	Dry Mouth	18.88 (25.28)	0.7532	0.5349	0.0446
	Trouble with Taste	16.92 (29.38)	0.6793	0.2238	0.6796
	Trouble with Coughing	4.30 (12.65)	0.5608	0.5070	0.5680
	Trouble Talking	2.76 (9.22)	0.7135	0.2025	0.0613
	Abbreviations: HRQOL, Health Related Quality of Life; SD, standard deviation; MC, Major Complication; MPC,
	Major Pulmonary Complication; OS, Overall Survival; QLQ-C30, European Organisation for Research and
	Treatment of Cancer Quality of Life Questionnaire Core 30; QLQ OES-18, European Organisation for Research
	and Treatment of Cancer-Esophageal Cancer module-18.

Table 4 .

 4 Multivariable analysis of the impact of baseline HRQOL on the occurrence of death at 1 year after surgery Under each model with HRQOL for the occurrence of death at 1 year.Abbreviations: HRQOL, Health Related Quality of Life; HR, Hazard Ratio.

		Pain		Insomnia
		HR [95% CI]	P value	HR [95% CI]	P value
	HRQOL *	1.23 [1.02;1.50]	0.035	1.16 [1.01;1.32]	0.031
	Age (year)
	≤ 60	1		1
	> 60	2.80 [1.10;7.15]	0.031	2.18 [0.87;5.48]	0.098
	Major complication
	No 1		1
	Yes 3.23 [1.36; 7.66]	0.008	2.99 [1.24;7.20]	0.015
	TNM-N
	N0	1		1
	N1	2.08 [0.86;5.04]	0.103	2.69 [1.05;6.93]	0.040
	N2	10.43 [2.37;45.87]	0.002	10.51 [2.30;47.90]	0.002
	*

functioning, at 91.82 (SD=12.17), and the lowest symptomatic score was trouble talking, at

Ratio; SCC, Squamous Cell Carcinoma; ASA, American Society of Anesthesiologists.216

Patients with higher role functioning scores (every 10 point) were at lower risk of MC 206 (HR=0.86; 95% CI [0.77-0.96]; P=0.007), while every 10-point increase in fatigue (HR=1. [START_REF] Clavien | Severity Grading of Surgical Complications[END_REF] Author statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.