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This article is protected by copyright. All rights reserved.

Research Article

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus1

Type of study: original article

Els Visser 0000-0002-4051-1046 0000-0002-4051-1046, MD*

David Edholm, MD, PhD*⁑

B. Mark Smithers, MBBS, FRACS, FRCSEng, FRCSEd*^§

Iain G. Thomson, MBBS, FRACS*^

Bryan H. Burmeister*^

Euan T. Walpole+^

David C. Gotley, FRACS, MD, PhD*^

Warren L. Joubert+

Victoria Atkinson^+

G. Tao Mai±

Janine M. Thomas, BsHSc*§

Andrew P. Barbour, MBBS, PhD, FRACS, FACS*^‡,

*Upper Gastrointestinal/Soft Tissue Unit, Discipline of Surgery, Princess Alexandra Hospital,

Woolloongabba, Queensland, Australia;

^The University of Queensland, Brisbane, Queensland, Australia;

1 This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1002/jso.25089

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⁑ Institution of Surgical Sciences, Uppsala University, Sweden;

§ Mater Medical Research Institute, Mater Health Services, Raymond Terrace, South Brisbane, Australia;

+ Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia;

± Radiation Oncology, Division of Cancer Services, Princess Alexandra Hospital, Woolloongabba,

Queensland, Australia;

‡ The University of Queensland, Diamantina Institute, Translational Research Institute, Woolloongabba,

Queensland, Australia;

Declarations of interest: None

Corresponding author at all stages of refereeing and publication: Els Visser, e.visser-3@umcutrecht.nl

Corresponding author post-publication: Andrew Barbour, a.barbour@uq.edu.au

Running head: nCT or nCRT for esophageal cancer

Keywords: esophageal carcinoma, neoadjuvant therapy, adenocarcinoma, outcome, survival

David Edholm received funding from Swedish medical council

SYNOPSIS

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For patients with esophageal adenocarcinoma (EAC), there are no differences between nCT and nCRT in

postoperative complications and in-hospital mortality. nCRT results in higher complete resection rates

and pathological response rates, without improving overall survival. This study indicates that if the focus

is on overall survival, the addition of radiotherapy is not necessary for patients with EAC.

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Abstract

Background

The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains

undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT)

and neoadjuvant chemoradiotherapy (nCRT) for EAC.

Methods

Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective

database (2000-2017) and included. After propensity score matching, the impact of the treatments on

postoperative complications, in-hospital mortality, pathological outcomes and survival rates were

compared.

Results

Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both

groups. There were no significant differences between the nCT and nCRT groups for overall

complications (59% vs 57%,p=0.802) or in-hospital mortality (2% vs 0%,p=0.156). Patients who had nCRT

had more R0 resections (93% vs 83%,p=0.013), and higher pathological complete response rates (15%

vs. 5%,p<0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%,p=0.645) were

found.

Conclusion

In this study no differences between nCT and nCRT were seen in postoperative complications and in-

hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological

response there was no difference in the overall survival between the treatment modalities.

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INTRODUCTION

Adenocarcinoma of the esophagus and esophago-gastric junction (EAC) incidence has risen faster than

any other cancer in Australia, USA, UK and other industrialized nations, with a more than 5-fold increase

over the last 4 decades.(1,2) Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT), have

shown survival benefits over surgery alone and have become the standard of care.(3,4) However

controversy exists regarding the optimal treatment strategy, particularly in regard to the additional

benefit of radiotherapy (RT) over chemotherapy alone.

The available studies comparing nCT and nCRT are equivocal with one randomized study(5) reporting a

trend for a survival benefit for patients who had nCRT, while other randomized(6,7) and non-

randomized(8,9) studies have shown no difference in survival from the addition of RT. However, the

studies have had limited sample size(5-7), have been underpowered(5-7) and used different

neoadjuvant regimens(5,7).

Additionally dose-limiting toxicity is a significant potential problem for patients undergoing pre-

operative therapy regimens. Concerns have been raised regarding toxicity that may occur from the

addition of RT to a chemotherapy regimen as well as a potential to increase the risk of postoperative

complications and mortality.(10,11)

With this ongoing need to define the role of pre-operative RT with respect to its impact of surgical

outcomes, patterns of recurrence and survival in patients with EAC, we assessed these outcomes for our

EAC patients who received nCT or nCRT followed by esophagectomy. Propensity score matching was

used to allow comparison of the outcomes to further define the role of the utility of nCRT.

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MATERIALS AND METHODS

Patients

From 1987 to April 2017 all patients with esophageal cancer managed at the Princess Alexandra

Hospital, Brisbane, Australia have been documented prospectively onto a computer database REDcap.

Patients with EAC, who received nCT or nCRT followed by esophagectomy between 2000 and 2017 were

included in this study. These patients were discussed at the upper GI oncology multidisciplinary tumor

board. To be considered for neoadjuvant therapy patients were clinically staged to be >cT2 or cN+

cT1,N>0 or >cT2N0 , and fit for esophagectomy. Patients have routinely been offered neoadjuvant

therapy either as part of a randomized clinical trial or following discussion in the multidisciplinary tumor

board. Ethics approval has been obtained for this study.(HREC/16/QPAH/614).

Pre-operative staging

All patients have been routinely staged with endoscopy and computed tomography (CT) scanning of the

thorax and abdomen. Fluoro-deoxyglucose positron emission tomography (FDG-PET) scanning began in

2005 and became the standard staging in our center by 2008. Selected patients had endoscopic

ultrasound assessment to clarify staging where this would influence the use of neoadjuvant therapy.

Treatment

The nCT regimen has been based on two cycles of cisplatin and 5-fluoruracil (5-FU) as per Medical

Research Council (MRC) OEO2-trial(12) or epirubicin, cisplatin, and 5-FU for three cycles before and

three cycles after esophagectomy, as per the MRC, MAGIC-trial protocol(3). Patients with EGJ Siewert II

EAC and good vital status were more often treated with MAGIC regimen. A small number of patients

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received docetaxel, cisplatin and infusion 5-FU (DCF) for 2 cycles pre-operatively. The most common

regimen of nCRT has been to administer external beam radiation therapy with 2 cycles cisplatin and 5-

FU at a dose of either 35 Gy in 15 fractions or 45 Gy in 25 fractions. A small number of patients received

DCF chemotherapy with 45 Gy in 25 fractions concurrent RT. Since 2015, there has been increasing use

of the CROSS regimen with the combination of 5 weekly cycles of carboplatin and paclitaxel given

concurrently with a RT dose of 41.4 Gy in 20 fractions(4).

The surgical techniques used in this study have been previously described.(13) In summary, patients had

a two-field approach (Ivor Lewis Thoraco-abdominal approach) if the tumor involved a significant

proportion of the stomach. A three-field approach (typically thoracoscopic mobilization with a cervical

anastomosis) was used if the tumor involved the mid or lower esophagus. The primary tumor was

dissected with a mediastinal lymphadenectomy including the inferior mediastinal nodes, subcarinal

nodes and the thoracic duct if a large tumor was present. In the abdomen the left gastric and common

hepatic l lymph node stations were dissected with a cuff of diaphragmatic hiatus for Siewert II type EAC.

A gastric conduit was constructed.

Postoperative complications

All postoperative complications were prospectively registered and graded, and were subclassified into

surgical and medical complications for this study which correspond with earlier series.(14-16) Surgical

complications included anastomotic leak, bleeding, chyle leak, wound infection, vocal cord palsy,

trachea-esophageal fistula and conduit necrosis. Medical complications were defined as respiratory,

cardiac, bacteriaemia/septicaemia, pulmonary embolism/deep vein thrombosis, urinary tract infection,

acute renal failure, and confusion. Respiratory complications included respiratory failure, pneumonia,

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atelectasis, pleural effusion, pneumothorax or acute respiratory distress syndrome. Cardiac

complications included atrial fibrillation, ischemia or failure.

Histopathology

The resected specimens were prepared in theatre with a member of the surgical team dissecting the

nodal tissue into separate labeled containers. Resection margins were evaluated according to the

College of American Pathologists.(17) Tumor stage was reviewed by experienced pathologists in

accordance with the AJCC TNM-staging system, 7th edition.(18) In addition, specimens were assessed

for tumor regression grade (TRG) using the Mandard score.(19)

Follow-up and Recurrence

After esophagectomy, patients were assessed every three months for the first two years, six months for

the next three years and then annually up to ten years. Investigations were directed at symptoms

suggestive of recurrent disease. The pattern of recurrence was classified as local, regional, distant or

combined. Local recurrence was defined as disease occurring at the anastomotic site or within the

previous esophageal bed. Regional recurrence was defined as disease occurring within the draining

lymphatic basins (lower cervical, mediastinal, and celiac), according to the 7th edition of staging manual

for esophageal cancer (18). Distant recurrence was defined as recurrent disease in organs suggestive of

hematogenous or transcoelomic spread. Recurrence was considered to have occurred if there was

histological proof or unequivocal radiological evidence of recurrence. When present in two locations it

was considered synchronous if detected within 30 days of each other.

Study outcomes and Statistics

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In order to avert the effect of confounding influences of covariates on outcomes between the two study

groups (nCT versus nCRT), propensity score matching was performed to create two comparable groups.

Propensity scores(20) were calculated using Stata® version 13.1 (Statacorp LP, Texas, USA). The

propensity scores were estimated on the baseline data of age, gender, comorbidities, history of

malignancy, American Society of Anesthesiologists (ASA)-classification, tumor location, tumor

differentiation, clinical staging, year of surgery, type of surgery and if FDG-PET scan was performed. A

pairwise propensity scores matching was used with caliper of 0.2 to obtain groups with evenly

distributed variables among study groups.

Primary outcome measures consisted of postoperative complications, in-hospital and 90-day mortality,

R0-resection rates, pathological T- and N-staging, TRG, overall survival (OS), and disease-free survival

(DFS). OS was defined as the time between surgery and death or last follow-up. DFS was defined as the

time between surgery and recurrence. For the purpose of analysis the site of symptomatic first

recurrence was used. For the patterns of recurrence, only patients with a follow-up of ≥24 months or

patients who developed recurrent disease <24 months were included.

To determine differences between the nCT and nCRT group regarding baseline data and outcomes, the

Chi square test was used for categorical variables, and the Students t-test or Mann-Whitney U-test for

parametric and non-parametric continuous data. Kaplan-Meier survival curves were constructed for

both treatment groups on OS and DFS and compared using the log-rank test. Data was analysed using

IBM SPSS Statistics Version 23.0 for Windows (IBM Corp., Armonk, NY). A p-value of <0.05 was

considered statistically significant.

RESULTS

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Patient population

A total of 396 consecutive patients with clinically >cT2 or cN+ cT1,N>0 or >cT2N0 EAC underwent nCT or

nCRT followed by esophagectomy in the study period and were included. In the original cohort

differences between the groups were observed in cN-stage (p=0.036) and if a diagnostic FDG-PET was

performed (p=0.001) (Table 1). After propensity score matching, 131 patients were assigned to each

group with all pretreatment characteristics being balanced (Table 1). Table 2 presents the different

treatment regimens for both groups.

Postoperative complications and in-hospital and 90-day mortality

There were no significant differences in overall postoperative complications between the nCT (n=77,

59%) and nCRT (n=75, 57%) group (p=0.802) (Table 3). In addition, no significant differences were found

in surgical (p=0.487) and medical (p=0.457) complications between the two groups. No difference in in-

hospital (p=0.156) and 90-day mortality (p=1.000) was observed between both groups (Table 3).

Pathological T- and N-stage, R Status and Tumor Regression Grade

A R0-resection was achieved in 109 patients (83%) in the nCT group, compared to 122 patients (93%) in

the nCRT group (p=0.013). Patients in the nCRT group had significantly more pathological down-staging

of T-stage (p=0.011) and N-stage (p=0.004) compared with patients in the nCT group. In addition, more

histologic regression was found after the addition of nCRT compared to nCT, reflected by significantly

lower Mandard-scores (p<0.001, Table 4).

Overall Survival

With a median follow-up period of 47 months (range 0-179), the median OS of the whole group of

patients was 22 months [range 0-179]. For the nCT cohort the median OS was 26 months [range 1-172],

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and 1-, 3-, and 5-years OS rates were 81%, 51%, and 44%. For the nCRT cohort the median OS was 21

months [range 0-179] and 1, 3 and 5 year OS rates were 79%, 47%, and 33%. There was no significant

difference between the groups (Figure 1, Logrank p=0.645).

Pattern of Recurrence

Recurrent disease occurred in 142 patients (54%) with 116 (82%) occurring within 24 months. For

patients with at least 24 months follow up, in the nCT group and nCRT group, 60 patients (61%) and 56

patients (61%) developed recurrent disease within 24 months, respectively (Table 5). No differences

between the groups were found in pattern of recurrence (p=0.753) (Table 5).

Disease-Free Survival

Median DFS of all patients was 17 months [range 0-179]. In the nCT group, median DFS was 18 months

[range 1-172], and 1-, 3-, and 5-years DFS rates were 68%, 43% and 39%. In the nCRT group, median DFS

was 15 months [range 0-179], and 1-, 3-, and 5-years DFS rates were 70%, 44% and 39%. No differences

in DFS were found between both treatment groups (Figure 2, Logrank p=0.879).

DISCUSSION

Along with improved staging and surgical outcomes, it is clear that the use of multimodality therapy has

improved survival for patients with EAC.(3,4) However the optimal treatment strategy remains

undetermined and the preferred neoadjuvant therapy including nCT or nCRT is not clear. This single-

centre cohort study investigated the influence of nCT and nCRT on outcomes in patients with advanced

EAC.

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It is previously demonstrated that the use of neoadjuvant therapies is associated with toxicity, and

contributes to an increase in postoperative complications and in-hospital mortality.(21) Analysis of

postoperative complications, in-hospital and 90-day mortality in the current study did not find

significant differences between the nCT and nCRT groups. For example, no negative effect of RT was

seen on anastomotic leak rates (nCT: 12%, nCRT: 10%), respiratory complications (nCT: 35%, nCRT: 35%)

or cardiac complications (nCT: 16%, nCRT: 19%). These findings are in line with two recent meta-

analyses comparing postoperative complications and mortality between patients treated with nCT or

nCRT for esophageal carcinoma.(22,23)

Three randomized trials(5-7) comparing nCT and nCRT, in patients with EAC, have not reported a

difference in OS between the two treatment regimens. However these studies were conducted with

relatively small sample sizes (n=75-181), yielding limited statistical power. In addition, other

neoadjuvant therapies were used(5,7), which may be inferior with regard to safety and postoperative

complications in comparison with the regimens used in the current study (OESO2(12), MAGIC(3), and

CROSS(4) regimens. Similarly, analyses in the non-randomized(8,9) setting with large national cancer

databases or with multi-institutional data have not found differences in OS. Although the above

mentioned trials did not find differences in survival between the two treatment groups, higher R0-

resection rates and pathologic complete response rates were found after treatment with nCRT.(5-8)

In this study propensity score matching(20) was performed to improve the comparability between the

nCT and nCRT groups with a larger number of patients. The results are in broad agreement with previous

studies. Compared to nCT, nCRT resulted in higher R0-resection rates (93% vs 83%) and more

pathological downstaging, including higher pathological complete response rates (15% vs 5%). Although

pathological staging is a major prognostic factor of survival(24-26), the current study showed that

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increased pathological downstaging did not translate into improved OS rates for the nCRT group

(p=0.645). These data are supported by the Scandinavian NeoRes trial, in which a major pathologic

response was reported to be 15% in the group having nCT and 52% in those having nCRT with no

improvement in OS.(7) In addition, we did not identify any differences in recurrence patterns between

the groups (p=0.959). Despite the difference in R0-resection rates, local tumor control was reasonable

with both nCT and nCRT which is reflected in a low percentage of local recurrences (nCT 2% vs nCRT 4%).

This study demonstrates that the majority of patients will develop distant, or combined recurrences

which develop outside the radiation field.

This study is one of the largest studies comparing nCT with nCRT at a single center. All patients were

discussed in a multidisciplinary meeting and the performed surgical techniques are standardized and

uniformly performed. Although propensity score matching was used, this study has a retrospective

character and lack of randomization. In addition, different neoadjuvant regimens have been used.

However, the majority of patients (93%) received well-known regimens according to the OEO2-trial(12)

or MAGIC-trial(3). Because median OS of all patients was 22 months, recurrence patterns were only

reported for patients with a median follow-up of 24 months. However, the majority of patients develop

recurrence within 2 years after surgery(27,28), and therefore the data were considered sufficient to

report the pattern of recurrence.

The results of this study suggests that local tumor control can be achieved with either nCT as nCRT

followed by esophagectomy with regional lymphadenectomy for patients with EAC. The addition of RT

to chemotherapy would seem most relevant for very locally advanced tumors in order to reduce the

technical challenges associated with esophagectomy. Prognostic differences between the two treatment

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strategies are small and the location of recurrence patterns indicates that there is a need for feasible

treatments that results in effective systemic tumor elimination of micrometastasis.

In conclusion, this study demonstrates no differences between nCT and nCRT in postoperative

complications and mortality in patients treated for advanced EAC. Although nCRT resulted in improved

R0-resections rates and higher pathological response rates, this did not translate into a survival benefit.

Therefore, it is reasonable to hypothesize that if the focus is on survival, RT is not necessary for patients

with EAC. RT may be of added value for those patients with larger cT3/4 cancers where cyto-reduction

may be beneficial for surgical removal. The data supports the role of a large randomized controlled trial

formally comparing nCT with nCRT.

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16. Ferri LE, Law S, Wong KH, Kwok KF, Wong J. The influence of technical complications on

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significance of circumferential resection margins in esophageal cancer. Arch Surg. 2009;144:618-624.

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19. Mandard AM, Dalibard F, Mandard JC, et al. Pathologic assessment oftumor regression after

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20. Rosenbaum PR and Rubin DB. The central role of the propensity score in observational studies for

causal effects. Biometrika. 1983; 70: 41-55.

21. Hamilton E, Vohra RS, Griffiths EA. What is the best neoadjuvant regimen prior to oesophagectomy:

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mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable

oesophageal and gastro-oesophageal junctional cancers. Br J Surg. 2014; 101:321–338

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23. Kumagai K, Rouvelas I, Tsai JA, et al. Survival benefit and additional value of preoperative

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24. Meredith KL, Weber JM, Turaga KK, et al. Pathologic response after neoadjuvant therapy is the major

determinant of survival in patients with esophageal cancer. Ann Surg Oncol. 2010; 17:1159–1167.

25. Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapy pathologic stage predicts survival in patients with

esophageal carcinoma receiving preoperative chemoradiation. Cancer. 2005; 103:1347–1355.

26. Donahue JM, Nichols FC, Li Z, et al. Complete pathologic response after neoadjuvant

chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg. 2009;

87:392–398. discussion 398-399.

27. Blom RL, Lagarde SM, van Oudenaarde K, et al. Survival after recurrent esophageal carcinoma has

not improved over the past 18 years. Ann Surg Oncol. 2013;20:2693–8.

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intent. Ann Surg Oncol. 2015;22 Suppl 3:1292–300.

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FIGURE LEGENDS

Figure 1. The influence of neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT)

on overall survival in patients who underwent esophagectomy for esophageal adenocarcinoma. Survival

curves were plotted by the Kaplan-Meier method. Logrank p=0.645.

Figure 2. The influence of neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT)

on disease-free survival in patients who underwent esophagectomy for esophageal adenocarcinoma.

Survival curves were plotted by the Kaplan-Meier method. Logrank p=0.879.

Table 1. Comparison of baseline characteristics of 396 patients who underwent neoadjuvant chemotherapy or chemoradiotherapy followed

by esophagectomy for esophageal adenocarcinoma, before and after propensity score matching

Original cohort Propensity score matched cohort

nCT + surgery nCRT +surgery nCT+ surgery nCRT + surgery

N=203 (%) N=193 (%) p-value N=131 (%) N=131 (%) p-value

Age [mean ± SD] 60.7 8.9 61.0 9.1 0.723 61.3 8.6 60.6 9.4 0.501

Gender 0.164 0.512

Male 180 (89) 179 (93) 118 (90) 121 (92)

Female 23 (11) 14 (7) 13 (10) 10 (8)

Comorbidities 0.174 0.901

No 120 (59) 101 (52) 72 (55) 73 (56)

Yes 83 (41) 92 (48) 59 (45) 58 (44)

Malignancy history 0.091 0.355

No 196 (97) 179 (93) 124 (95) 127 (97)

Yes 7 (3) 14 (7) 7 (5) 4 (3)

ASA 0.644 0.703

1 15 (7) 7 (4) 7 (5) 7 (5)

2 136 (67) 146 (76) 91 (70) 94 (72)

3 52 (26) 39 (20) 33 (25) 30 (23)

Missing 0 (0) 1 (<1)

Tumor location 0.207 0.943

Middle third 4 (2) 10 (5) 4 (3) 5 (4)

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Lower third 109 (54) 104 (54) 72 (55) 71 (54)

EGJ 90 (44) 79 (41) 55 (42) 55 (42)

Tumor differentiation 0.600 0.423

Well 4 (2) 4 (2) 3 (2) 2 (2)

Moderate 63 (31) 69 (36) 48 (37) 39 (30)

Poor 136 (67) 120 (62) 80 (61) 90 (69)

Clinical T-stage 0.204 0.883

cT1 8 (4) 5 (3) 4 (3) 1 (1)

cT2 81 (40) 68 (35) 47 (36) 50 (38)

cT3 114 (56) 120 (62) 80 (61) 80 (61)

cT4 0 (0) 0 (0) 0 (0) 0 (0)

Clinical N-stage 0.036 0.878

cN0 135 (67) 110 (57) 83 (63) 85 (65)

cN1 63 (31) 72 (37) 44 (34) 40 (31)

cN2-3 5 (3) 11 (6) 4 (3) 6 (5)

Year of surgery, median [range] 2014 [2001-2017] 2016 [2000-2017] 0.195 2009 [2001-2017] 2010 [2000-2017] 0.527

Type of surgery 0.115 0.890

Open 55 (27) 45 (23) 32 (24) 33 (25)

Minimally invasive 25 (12) 14 (7) 11 (8) 13 (10)

Hybrid 123 (61) 134 (69) 88 (67) 85 (65)

Diagnostic FDG-PET performed 0.001 0.848

Yes 185 (91) 153 (79) 115 (88) 116 (89)

No 18 (9) 40 (21) 16 (12) 15 (12)

Data are numbers of patients with percentages in parentheses. Bold values means statistically significant (p<0.05). nCT: neoadjuvant

chemotherapy, nCRT: neoadjuvant chemoradiotherapy; ASA: American Society of Anesthesiologists EGJ: Esophageal gastric junction, SD:

standard deviation

Table 2. Description of chemotherapy and radiotherapy regimen of 262

patients who underwent neoadjuvant chemotherapy or chemoradiotherapy

followed by esophagectomy for esophageal adenocarcinoma

nCT + surgery nCRT +surgery

N=131 (%) N=131 (%)

Chemotherapy regimen

Cisplatin + 5-FU 92 (70) 94 (72)

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Epirubicin, Cisplatin, 5-FU 30 (23) 2 (2)

Carboplatin + Paclitaxel 0 (0) 20 (15)

Other 9 (7) 15 (11)

Radiotherapy dose

35 Gy n.a. 69 (53)

41 Gy n.a. 14 (11)

45 Gy n.a. 40 (31)

Other n.a. 8 (6)

nCT: neoadjuvant chemotherapy, nCRT: neoadjuvant chemoradiotherapy,

5-FU: 5-fluoruracil, n.a.: not applicable

Table 3. Comparison of complications of 262 patients who underwent neoadjuvant

chemotherapy or chemoradiotherapy followed by esophagectomy for esophageal

adenocarcinoma

nCT + surgery nCRT +surgery

N=131 (%) N=131 (%) p-value

Any complication 0.802

No 54 (41) 56 (43)

Yes 77 (59) 75 (57)

Surgical complication 0.487

No 93 (71) 98 (75)

Yes 38 (29) 33 (25)

Anastomotic leak 16 (12) 13 (10)

Bleeding 0 (0) 2 (2)

Chyle leak 4 (3) 8 (6)

Wound infection 12 (9) 8 (6)

Vocal cord palsy 6 (5) 0 (0)

Trachea-esophageal fistula 3 (2) 0 (0)

Conduit necrosis 3 (2) 1 (<1)

Other 1 (<1) 3 (2)

Medical complication 0.457

No 74 (57) 68 (52)

Yes 57 (44) 63 (48)

Respiratory 46 (35) 46 (35)

Cardiac 21 (16) 25 (19)

Bacteriaemia/septicaemia 4 (3) 4 (3)

PE/DVT 2 (2) 2 (2)

Urinary tract infection 1 (<1) 2 (2)

Acute renal failure 2 (2) 1 (<1)

Confusion 3 (2) 4 (3)

Other 0 (0) 0 (0)

In-hospital mortality 0.156

No 129 (99) 131 (100)

Yes 2 (2) 0 (0)

90-day mortality 1.000

No 128 (98) 128 (98)

Yes 3 (2) 3 (2)

Length of hospital stay (days) median

[range]

13 [7-97] 13 [7-75] 0.772

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[range]

nCT: neoadjuvant chemotherapy, nCRT: neoadjuvant chemoradiotherapy, PE= pulmonary

embolism, DVT= deep venous thrombosis

Table 4. Comparison of pathology of 262 patients who underwent neoadjuvant

chemotherapy or chemoradiotherapy followed by esophagectomy for esophageal

adenocarcinoma

nCT + surgery nCRT +surgery

N=131 (%) N=131 (%) p-value

Radicality 0.013

R0 109 (83) 122 (93)

R1 22 (17) 9 (7)

Lymph node yield, median [range] 26 [8-83] 21 [4-58] <0.001

Pathological T-stage 0.011

ypT0 6 (5) 20 (15)

ypT1 26 (20) 21 (16)

ypT2 16 (12) 24 (18)

ypT3 75 (57) 64 (49)

ypT4 8 (6) 2 (2)

Pathological N-stage 0.004

ypN0 43 (33) 63 (48)

ypN1 37 (28) 35 (27)

ypN2 30 (23) 22 (17)

ypN3 21 (16) 11 (8)

Positive nodes, median [range] 0 [0-18] 0 [0-15] 0.007

Mandard <0.001

1 6 (5) 20 (15)

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2 12 (9) 41 (32)

3 28 (22) 37 (29)

4 52 (41) 21 (16)

5 29 (23) 11 (9)

Missing 4 1

nCT: neoadjuvant chemotherapy, nCRT: neoadjuvant chemoradiotherapy. Bold values

means statistically significant (p<0.05)

Table 5. Comparison of recurrence pattern of 191 patients who underwent

neoadjuvant chemotherapy or chemoradiotherapy followed by esophagectomy for

esophageal adenocarcinoma

nCT + surgery nCRT +surgery

N=99 (%) N=92 (%) p-value

Recurrence 0.970

No 39 (39) 36 (39)

Yes 60 (61) 56 (61)

Pattern of recurrence 0.753

Local 1 (2) 1 (2)

Loco-regional 10 (17) 6 (11)

Distant 36 (60) 36 (64)

Local & loco-regional 0 (0) 0 (0)

Local & distant 0 (0) 0 (0)

Loco-regional & distant 13 (22) 12 (21)

All 0 (0) 1 (2)

nCT: neoadjuvant chemotherapy, nCRT: neoadjuvant chemoradiotherapy. Only

patients with a follow-up of ≥24 months or patients who developed recurrent disease

<24 months were included.

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Figure-1DPI_1200 .

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Figure-2DPI_1200 .