Prognostic differences in 8th edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment

Prognostic differences in 8th edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment

Accepted Manuscript th Prognostic differences in 8 edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment Leila Sisic, MD, ...

2MB Sizes 0 Downloads 0 Views

Accepted Manuscript th Prognostic differences in 8 edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment Leila Sisic, MD, Thomas Schmidt, MD PhD, Susanne Blank, MD, Henrik Nienhueser, MD, Sara Dorr, Georg Martin Haag, MD, Dirk Jäger, MD, Thomas Bruckner, Beat P. Müller-Stich, MD, Katja Ott, MD, Markus W. Büchler, MD, Alexis Ulrich, MD PII:

S0748-7983(18)31174-0

DOI:

10.1016/j.ejso.2018.06.030

Reference:

YEJSO 5020

To appear in:

European Journal of Surgical Oncology

Received Date: 29 October 2017 Revised Date:

5 April 2018

Accepted Date: 27 June 2018

Please cite this article as: Sisic L, Schmidt T, Blank S, Nienhueser H, Dorr S, Haag GM, Jäger D, th Bruckner T, Müller-Stich BP, Ott K, Büchler MW, Ulrich A, Prognostic differences in 8 edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment, European Journal of Surgical Oncology (2018), doi: 10.1016/j.ejso.2018.06.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

ACCEPTED MANUSCRIPT

Original article: Prognostic differences in 8th edition TNM staging of esophagogastric adenocarcinoma after

Running title: (y)pTNM-staging in esophagogastric adenocarcinoma

RI PT

neoadjuvant treatment

SC

Leila Sisic MD1*, Thomas Schmidt MD PhD1*, Susanne Blank MD1, Henrik Nienhueser MD1, Sara Dorr1, Georg Martin Haag MD2, Dirk Jäger MD2, Thomas Bruckner3, Beat P. Müller-Stich

M AN U

MD1, Katja Ott MD4, Markus W. Büchler MD1, Alexis Ulrich MD1 1

Department of Surgery, University Hospital Heidelberg, Heidelberg 69120, Germany

2

Department of Medical Oncology, National Center for Tumor diseases (NCT), University Hospital

Heidelberg, Heidelberg 69120, Germany

Institute for medical biometrics and informatics (imbi), University Hospital Heidelberg, Heidelberg

TE D

3

69120, Germany

Department of Surgery, RoMed Hospital Rosenheim, Rosenheim 83022, Germany

EP

4

AC C

*These authors contributed equally

Corresponding author:

Thomas Schmidt, MD, PhD

Im Neuenheimer Feld 110, 69120 Heidelberg, Germany E-Mail: [email protected] Tel.: 0049-6221-5636658 Fax: 0049-6221-566988

2

ACCEPTED MANUSCRIPT Abstract: Background:

Prognostic differences between pTN- and ypTN-categories and the prognostic accuracy of the 8th edition UICC-pTNM- and AJCC-ypTNM-staging-system for esophageal and gastric adenocarcinoma

RI PT

are unclear. Methods:

We retrospectively analyzed data of 740 patients with esophagogastric adenocarcinoma, who

SC

underwent curative surgery (344 after neoadjuvant treatment [NT]) at our institution. Survival analyses were performed according to Kaplan-Meier (log-rank test). Multivariate analyses were

M AN U

performed using the Cox proportional hazard model. Results:

Low ypT-categories did not discriminate overall survival (ypT0: reference; ypT1: HR1.0/p=0.909; ypT2: HR0.9/p=0.845; ypT3: HR1.5/p=0.184; ypT4: HR2.8/p=0.004) and no difference was found

TE D

between ypN1- and ypN2-disease (ypN0: HR0.4/p<0.001; ypN1: reference; ypN2: HR1.1/p=0.653; ypN3: HR1.7/p=0.014). In esophageal adenocarcinoma the UICC-TNM- and AJCC-ypTNM-stagingsystem was able to predict survival for patients after NT, while in gastric cancer it failed to provide

EP

sufficient prognostic information. A simplified staging system provided better stratification after NT and was an independent prognosticator for both esophageal and gastric adenocarcinoma (stage I:

AC C

reference; stage II: HR2.2/p=0.005; stage III: HR4.1/p<0.001). Conclusion:

Prognostic value of ypTN-categories seems limited. After NT the current UICC/AJCC-staging-system is able to predict survival in esophageal adenocarcinoma, but needs to be reevaluated in gastric cancer patients and modified if needed. A novel simplified staging system might be more practicable for patients after NT. Keywords: Gastric cancer, esophageal cancer, neoadjuvant treatment, staging, prognosis

3

ACCEPTED MANUSCRIPT

Abbreviations: AEG AIC AJCC CT EC EAC GC IGCA NCDB NT OS pCR PS SBC THG UICC WECC

AC C

EP

TE D

M AN U

SC

RI PT

Adenocarcinoma of the esophago-gastric junction Akaike Information Criterion American Joint Committee on Cancer Computerized tomography Esophageal cancer Esophageal adenocarcinoma Gastric cancer International gastric cancer collaboration National Cancer Database Neoadjuvant treatment Overall survival Pathological complete response Primary surgery Schwarz Bayesian Information Criterion Transhiatal extended gastrectomy Union Internationale Contre le Cancer Worldwide esophageal cancer collaboration

4

ACCEPTED MANUSCRIPT 1. Introduction

Previously data collection for staging of esophageal and gastric cancer (EC, GC) has focused on data of patients after primary resection, while patients undergoing neoadjuvant treatment (NT) were excluded from the analyses. Even data-driven staging according to 7th edition of the UICC/AJCC-

RI PT

staging-system of 2010 for EC and GC was based on patients treated by surgery only [1-3]. However, as most patients are diagnosed with advanced tumor stages, the proportion of patients receiving NT before surgery has increased markedly over the past decade, nowadays representing the

SC

majority of EC and GC patients in Europe [4].

NT can influence T- and N-category by potential downstaging. Biological tumor selection by NT

M AN U

makes a direct comparison of pTN- and ypTN-category problematic. Smaller series and registry studies have indicated that the 7th edition of the UICC/AJCC-staging-system might not adequately predict survival for EC patients after neoadjuvant therapy [5-9].

In January 2017 the TNM-staging-system of the UICC 8th edition has been implemented. Clinical stage groups have been added, however, the 8th edition of the UICC-TNM-staging-system still does

TE D

not provide a separate staging system for patients having undergone neoadjuvant therapy [10]. The AJCC staging manual 8th edition will not be implemented until January 2018. For the first time, it provides a separate pathological staging system for EC and GC patients, who underwent surgery after

EP

NT [11]. This ypTNM-staging-system is based on recently published Worldwide Esophageal Cancer

AC C

Collaboration (WECC) staging data of 7,773 EC patients after NT followed by resection, which is the first analysis of pathological staging data in a large neoadjuvantly treated patient collective [12, 13]. Even though for the 8th edition of the UICC/AJCC-staging-system for GC data of more than 25,000 patients has been collected by the International Gastric Cancer Association (IGCA) staging project, again patients after neoadjuvant therapy were excluded [14]. Therefore, unfortunately an analysis of a comparable cohort of GC patients after NT followed by surgery is not available. The ypTNM-stagingsystem for GC was based on National Cancer Database (NCDB) data (n=683) of patients, who underwent surgical resection and were given NT [11].

5

ACCEPTED MANUSCRIPT

Aim of this study was to evaluate, whether ypTN- and pTN-category differ with regard to prognosis. Furthermore, we explored the prognostic accuracy of the 8th edition UICC-pTNM-staging-system and AJCC-ypTNM-staging-system for esophageal adenocarcinoma (EAC) and GC in a large single-center

AC C

EP

TE D

M AN U

SC

RI PT

population of patients including those receiving multimodal treatment.

6

ACCEPTED MANUSCRIPT 2. Patients and methods 2.1 Study Design and Patient Population

A total of 795 patients with primary invasive adenocarcinoma of the esophago-gastric junction (AEG type I, II, or III according to Siewert-classification) or stomach without distant metastases (M0)

RI PT

underwent elective surgery with curative intent at the University Hospital of Heidelberg, Department of Surgery between 2001 and 2015. A total of 55 patients were excluded from the analysis, 37 due to postoperative death (90-day-mortality 4.6%), and 18 because no follow-up information was available.

SC

Clinicopathological and follow-up data of the remaining 740 patients were collected in a prospective database and analyzed retrospectively (supplement figure 1). The conduct of this retrospective study

M AN U

was approved by the institutional ethics committee.

Patients were diagnosed by endoscopy with biopsies and CT-scan of the chest and upper abdomen. All patients with GC received NT in form of chemotherapy, whereas in EAC NT was administered in form of chemotherapy (90.5%), chemoradiotherapy (6.3%), or radiotherapy (2.6%). Details on NT are

TE D

listed in supplement table 1. Standard surgical procedures were a right abdominothoracic en-bloc esophagectomy with a 2-field lymphadenectomy (Ivor-Lewis procedure) for AEG I, a transhiatal extended gastrectomy (THG) with an extended D2-lymphadenectomy for AEG III or proximal GC,

EP

total gastrectomy with D2-lymphadenectomy for tumors in the middle or distal third of the stomach, and a subtotal gastrectomy for distal GC, if an adequate proximal resection margin was possible. AEG

AC C

II were treated either like AEG I or III depending on tumor extension into the esophagus [15]. Adjuvant treatment was administered in form of perioperative treatment, if patients had undergone neoadjuvant treatment [16]. A postoperative adjuvant treatment without previous neoadjuvant therapy was only recommended as individual treatment decision.

2.2 Histopathology and postoperative Staging Resection specimens were histologically examined in the Department of Pathology. Histopathologic work up included extent of primary tumor, regional lymph node spread, presence of distant metastases ((y)pTNM-categories according to the UICC-classification, 8th edition of 2017), R-category, tumor

7

ACCEPTED MANUSCRIPT

differentiation, and growth pattern according to Laurén. Tumors were classified as esophageal or gastric adenocarcinoma according to the definition of the UICC TNM classification of malignant tumors 8th edition. Specimens analyzed before 2017 were re-classified according to the 8th edition of the TNM-staging-system respectively. Tumor stage was documented according to the UICC-pTNM-

RI PT

staging-system (8th edition) for all patients, and according to the AJCC-ypTNM-staging-system (8th edition) for patients receiving neoadjuvant therapy (supplement table 2).

SC

2.3 Follow-up

Patients were followed on outpatient basis by our Medical Oncology Department or other treating

M AN U

physicians as previously published [17]. Complete follow-up information was available for all patients. The median follow-up time for surviving patients (n=410) was 59.7 months [17].

2.4 Statistical analysis

TE D

Overall survival (OS) was calculated from time of diagnosis till death or last follow-up date. Survival rates were estimated using the Kaplan-Meier method. Differences in survival amongst groups were estimated using the log-rank test. Prognostic factors were evaluated in a univariate and multivariate

EP

analysis using the Cox regression model. To compare categorical variables, we used the χ2 test.

AC C

The Akaike Information Criterion (AIC) and Schwarz Bayesian Information Criterion (SBC) were used in order to estimate the goodness-of-fit of each staging system as previously published [18]. All tests were two-sided and a p-value <0.05 was considered as statistically significant. Analyses were performed using SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA).

8

ACCEPTED MANUSCRIPT 3. Results 3.1 Baseline characteristics

The median age at time of diagnosis was 64 (range 27-90) years. 363 patients (49.1%) were diagnosed with EAC and 377 (50.9%) with GC. NT was administered to 190 (52.3%) EAC patients and to 154

RI PT

(40.8%) GC patients. Baseline characteristic showed significant heterogeneity between patients with primary surgery (PS) and those receiving NT. Detailed information on patient demographics, tumor

M AN U

3.2 Survival according to pathological T- and N-category

SC

characteristics, and treatment is summarized in table 1a+b.

Upon last follow-up 330 of 740 patients (44.6%) had died. Median OS (mOS) was 84.9 (95% CI 64.4105.3) months. Estimated 3- and 5-year OS rate was 64.0% and 53.7%.

After PS pT- and pN-category were prognostically relevant (mOS: pT1: not reached, pT2: 103.8, pT3: 37.5, pT4: 22.9 months, p<0.001; pN0: not reached, pN1: 123.6, pN2: 38.4, pN3: 19.5 months,

TE D

p<0.001). pT- and pN-categories correlated with outcome as expected (table 2, figure 1a+b). In patients who underwent NT ypT- and ypN-category were also significant prognostic factors (mOS: ypT0: 97.2, ypT1: 120.1, ypT2: not reached, ypT3: 52.1, ypT4: 22.3 months, p=0.002; ypN0: 120.1,

EP

ypN1: 39.3, ypN2: 37.7, ypN3: 26.4 months, p<0.001). However, ypT-category did not show the expected discrimination of prognosis. Locally limited tumors (ypT0/1/2) did not differ with regard to

AC C

prognosis, and prognostic difference between ypT0/1/2- and ypT3-tumors was moderate (table 2a, figure 1c). Also, in case of nodal positive disease distinction between individual ypN-categories was less marked with ypN1- and ypN2-disease showing equivalent outcome (table 2a, figure 1d).

9

ACCEPTED MANUSCRIPT 3.3 Comparison of pTN- with ypTN-categories

Within the individual pathological T-categories pT1 showed significantly better prognosis than ypT1 and ypT0 (mOS: pT1: not reached, ypT1: 120.1, ypT0: 97.2, p<0.001) (supplement figure 2a), while there was no significant difference between pT2 and ypT2 (mOS: 103.8 months vs. not reached,

RI PT

p=0.661) (supplement figure 2b), pT3 and ypT3 (mOS: pT3: 37.5, ypT3: 52.1 months, p=0.092) (supplement figure 2c), pT4 and ypT4 (mOS: pT4 22.9, ypT4: 22.3 months; p=0.949) (supplement figure 2d).

SC

Within the individual pathological N-categories there was a significant prognostic difference between pN0 and ypN0 (mOS: pN0: not reached, ypN0 120.1 months, p=0.039) (supplement figure 3a), pN1

M AN U

and ypN1 (mOS: pN1: 123.6, ypN1 39.3 months, p=0.048) (supplement figure 3b), but not pN2 and ypN2 (mOS: pN2: 38.4, ypN2: 37.7 months, p=0.988) (supplement figure 3c), pN3 and ypN3 (mOS: pN3: 19.5, ypN3: 26.4 months, p=0.142) (supplement figure 3d).

TE D

3.4 Survival according to tumor stage

After PS UICC-pTNM-stage discriminated well the long term prognosis in EAC and GC (p<0.001, respectively) (table 2b+c, figure 2a+b). In EAC differentiation between stage IA and IB as well as

EP

IIIA and IIIB further improved prognostication (supplement figure 4a), whereas in GC the prognostic difference between substages IA/IB, IIA/IIB, and IIIA/B was small (supplement figure 4b).

AC C

After NT prognostication by UICC-pTNM-stages was acceptable in EAC (p<0.001) (table 2b, figure 2c). Histopathologic complete responders (ypT0) who are not included in the UICC-pTNM-stagingsystem showed intermediate prognosis (table 2b, figure 2c). Differentiation between UICC-pTNMstage IIIA and IIIB improved prognostication (supplement figure 4c). In GC the UICC-pTNM-staging-system was not able to predict long term prognosis after neoadjuvant treatment, since there was no clear distinction between stage I and II, only stage III showed clearly poorer outcome (p<0.001) (table 2c, figure 2d). Patients without residual primary tumor after neoadjuvant therapy (ypT0) who are not classified according to UICC-staging had intermediate

10

ACCEPTED MANUSCRIPT

outcome (table 2c, figure 2d). Additional separation of UICC-stage I, II, and III into substages did not result in better stratification of patients (supplement figure 4d). The ypTNM-AJCC-staging-system also correlated with prognosis for EAC after neoadjuvant therapy (p<0.001) (table 2b, figure 2e, supplement figure 4e). However, stage I and II did not show a very

RI PT

marked prognostic distinction (figure 2e). Distinction between AJCC-ypTNM-stage IIIA and IIIB did not improve stratification of patients (supplement figure 4e). In GC the AJCC-ypTNM-stagingsystem is equivalent to the UICC-pTNM-staging-system, if substages are summarized to stage I, II,

SC

and III (figure 2d), still not providing a classification for patients with complete primary tumor

M AN U

regression (ypT0).

3.5 Survival according to simplified staging system for patients after neoadjuvant treatment According to our findings with lack of distinction among stage groups I and II of the AJCC-ypTNMstaging-system, we investigated whether a, simpler stage grouping could better stratify patients who

TE D

underwent neoadjuvant treatment. According to univariate Cox regression analysis of ypT-categories no significant prognostic difference was found between ypT0-3 categories and only ypT4 tumors had significantly poorer outcome (ypT0: reference; ypT1: HR 1.0 95%CI 0.4-2.2 p=0.909; ypT2: HR 0.9,

EP

95%CI 0.4-2.0, p=0.845; ypT3: HR 1.5, 95%CI 0.8-2.5, p=0.184; ypT4: HR 2.8, 95%CI 1.4-5.6, p=0.004). Univariate Cox regression analysis of ypN-categories showed significant prognostic

AC C

difference between ypN0-, ypN1/2-, and ypN3-disease (ypN0: reference; ypN1: HR 2.3, 95%CI 1.53.6, p<0.001; ypN2: HR 2.6, 95%CI 1.6-4.3, p<0.001, ypN3: HR 4.0, 95%CI 2.6-6.0, p<0.001) without prognostic difference between ypN1 and ypN2 when compared directly (ypN1: reference; ypN2: HR 1.1, 95%CI 0.7-1.9, p=0.653). Therefore, we summarized ypT0-3 and ypN1-2 categories (ypT0-3: reference; ypT4: HR 2.1, 95%CI 1.4-3.4, p=0.001; ypN0: reference, ypN1/2: HR 2.4, 95%CI 1.6-3.6, p<0.001; ypN3: HR 4.0, 95%CI 2.6-6.1, p<0.001) and modified the AJCC-ypTNM-stagingsystem for EAC accordingly by summary of ypTNM-stage I and II as well as stage IIIA and IIIB. This simplified staging system (table 3) showed good prognostic stratification of patients after NT for both EAC and GC (table 2b+c, figure 5a+b).

11

ACCEPTED MANUSCRIPT 3.6 Multivariate survival analyses in patients after neoadjuvant treatment

Multivariate analysis for patients receiving neoadjuvant therapy included the following factors: age, gender, tumor localization, tumor grading, R-category, adjuvant treatment, UICC-pTNM-staging,

RI PT

AJCC-ypTNM-staging, and suggested simplified staging. Age > 70 years (age ≤ 45 years: reference, age 46-69 years: HR 1.3, 95%CI 0.5-3.6, p=0.612; age > 70 years: HR 2.7, 95%CI 1.2-3.4, p=0.006) and the suggested simplified staging system (stage I: reference; stage II: HR 2.2, 95%CI 1.3-3.9,

SC

p=0.005; stage III: HR 4.1, 95%CI 2.2-7.3, p<0.001) were independent predictors of overall survival in EAC, while incomplete tumor resection (R0: reference; Rx/1: HR 2.2, 95%CI 1.2-4.1, p=0.012) and

M AN U

the suggested simplified staging system (stage I: reference; stage II: HR 2.4, 95%CI 1.3-4.5, p=0.006; stage III: HR 4.5, 95%CI 2.3-9.0, p<0.001) were selected as independent prognostic factors in GC.

3.7 Comparison of staging systems in patients after neoadjuvant treatment

TE D

The performance of the UICC-pTNM-, AJCC-ypTNM-, and suggested simplified staging system in neoadjuvantly treated patients was assessed by AIC and SBC. In EAC the suggested simplified staging system showed the lowest values of AIC and SBC indicating superior model fit, whereas in GC the

EP

suggested simplified staging system showed higher values of AIC and SBC than the UICC-

AC C

pTNM/AJCC-ypTNM-staging-system (supplement table 3).

12

ACCEPTED MANUSCRIPT 4. Discussion

With the recent release of the 8th edition of the UICC/AJCC-TNM-classification, for the first time the AJCC introduced a separate ypTNM-staging-system for EC and GC patients after NT. This study evaluated prognostic differences between ypTN- and pTN-categories and explored the prognostic

RI PT

accuracy of the 8th edition UICC-pTNM-staging-system and AJCC-ypTNM-staging-system for EAC and GC after NT.

We could show that pTN- and ypTN-categories are not equivalent with regard to prognosis. While

SC

after primary surgery pathological T- and N-categories showed the expected association with outcome, ypT- and ypN-categories did not reveal the expected prognostic stratification. No prognostic

M AN U

difference between ypT0-2 was detected and only ypT4 showed a significantly worse survival. Moreover, there was no clear prognostic distinction between ypN1- and ypN2-disease. In concordance with our results Metha et al. found no prognostic difference between ypT0-3- and ypN1/2-categories in 243 lower EC patients after neoadjuvant chemotherapy [7] and

several other studies have

demonstrated a lack of prognostication by ypT-category after NT [9, 19-23].

TE D

Possibly depth of tumor invasion lacks prognostic significance after NT, because residual tumor cells may persist in any layer of the esophageal or gastric wall without continuous growth from the mucosal layer. A large proportion (40-56%) of patients with less than 10% residual tumor still show advanced

EP

primary tumor categories (ypT3/4) [24, 25]. Hence, an advanced ypT-category does not necessarily

AC C

imply a high residual tumor burden.

Corresponding of pathological T-categories showed that pT1-category had markedly better outcome than ypT0 and ypT1. This can be explained as early esophagogastric cancers (pT1) have an excellent prognosis, while ypT0- and ypT1-carcinomas result from initially advanced tumors and do not reach the excellent outcome of early cancers, while still showing better survival than advanced patients not receiving NT. No significant difference could be detected between PS and NT within pathological T2-, T3-, and T4-categories. Since about 90% of neoadjuvantly treated patients had locally advanced tumors, most of ypT0-2 from initially more advanced tumors. So the benefit of NT shows, when comparing outcome of ypT0-2 tumors with prognosis of pT3-tumors, which was clearly worse.

13

ACCEPTED MANUSCRIPT

Downstaging of T- and N-category after NT has been previously shown to be associated with improved survival [26-28]. Complete pathologic responders (ypT0) showed no prognostic advantage compared to those with ypT1- and even ypT2-tumors. On the first look, this seems surprising, since many studies have

RI PT

promoted pathologic complete response (pCR) to NT as indicator of excellent outcome [29-34]. However, the outcome of ypT0 in our study is comparable with that in other series [33-36]. One possible explanation is that tumors with a high proliferation rate which have potentially aggressive

SC

tumor biology are most likely to respond to NT. In this case, remaining vital tumor or occult micrometastatic disease with aggressive tumor biology would be associated with high risk for recurrence

M AN U

and subsequently poorer outcome.

In our collective pN0 had better prognosis than ypN0 and pN1was more favorable than ypN1, while there was no difference between NT and PS within pathological N2- and N3-stage. Our results go in line with WECC-data exhibiting worse survival for node-negative disease after NT (ypN0) compared to primary surgery (pN0) [13]. However, nodal involvement still seems to be crucial as predictor of

TE D

prognosis after NT [7-9, 19-23, 36].

After PS we could validate the UICC-TNM-staging-system 8th edition for both EAC and GC. In neoadjuvantly treated EAC we could show, that prognostication by 8th edition UICC-pTNM-stage was

EP

acceptable. Only stage I did not show the expected good survival, probably because the sample size of

AC C

this subgroup was too small to provide reliable results. WECC-data revealed that prognosis of ypTNM-stage-groups IIIA-IVB was equivalent to the corresponding pTNM-stage-groups, while survival of early and intermediate ypTNM-stages clearly differed from that of equivalent pTNMgroups [12]. While 70% of EAC in our collective presented with advanced pathological UICC-stage (III/IV), unfortunately the number of patients with limited tumor stage after NT was too small to draw any conclusion on applicability of UICC-pTNM-staging for earlier stage disease. Furthermore, application of UICC-pTNM-staging left 13.7% of patients with pCR un-classified. Depending on NT regimen and modality the rate of pCR in EAC respresents a relevant proportion and is reported to be up to 23% [37-39]. Applying the AJCC-ypTNM-staging-system to EAC showed adequate

14

ACCEPTED MANUSCRIPT

stratification including those without residual tumor after NT, and therefore should be preferred over UICC-pTNM-staging for patients receiving neoadjuvant therapy. In GC patients who underwent NT the UICC-pTNM-staging-system did not satisfactory prognosticate survival due to lack of distinctiveness between stage I and II and between substages IIIA/B/C. The

RI PT

AJCC-ypTNM-gastric-cancer-staging-system did not provide a superior prediction of survival also lacking a prognostic distinction between stage I and II. Our results are conflicting with a recently published study in GC patients after preoperative chemoradiation [40], leaving prognostic relevance of

SC

ypTNM-staging in GC after NT uncertain. However, both classification-systems do not encompass ypT0 tumors. Even though response to NT generally seems to be less frequent in GC compared to

M AN U

AEG [41], a pCR rate of 15% was achieved in gastric cancer after chemotherapy by application of FLOT-protocol [42]. Hence, a separate ypTNM-staging-system without definition of ypT0-tumors is unacceptable. Since the AJCC-ypTNM-staging-system for GC was based on the data of not even 700 patients with a median follow-up of only 23 months, its validity seems questionable. Our simplified staging-system was an independent prognostic factor for EAC and GC, even when

TE D

UICC-pTNM- and AJCC-ypTNM-staging-systems were entered in multivariate analysis, indicating certain superiority in prediction of survival. However, assessment of the prognostic performance of our proposed staging system by AIC and SBC after NT revealed potentially superior model fit in

EP

EAC, but not in GC, possibly due to heterogeneity within stage groups. Separating only three stage groups represents a rough but solid staging-system. On the one hand, an overly simplified staging

AC C

system does not allow for adequate discrimination of heterogeneity within a stage group. On the other hand, an overly exact staging system with a large number of subgroups results inexpedient for routine clinical application. Superiority of the simplified staging-system in our collective might be due to statistical effects because of low patient numbers. Our proposed staging-system should be evaluated in a large cohort of esophagogastric adenocarcinoma patients after NT followed by surgery. This study has limitations to consider when interpreting its results. Since this is a retrospective analysis including patients from 2001-2015 there is heterogeneity between patients with regard to NT. Yet, a staging-system ideally should be applicable universally irrespective of treatment. Thus, the treatment heterogeneity reflects clinical reality. The single center study design resulted in a limited

15

ACCEPTED MANUSCRIPT

number of patients rendering the analysis of substages difficult or impossible due to small sample size

AC C

EP

TE D

M AN U

SC

RI PT

of subgroups.

16

ACCEPTED MANUSCRIPT 5. Conclusion

Prognostic value of ypTN-category seems limited after NT, since a lower ypT-category does not correlate with better prognosis and no prognostic difference was found between ypN1- and ypN2disease. In comparison to early esophagogastric cancer (pT1) with excellent prognosis ypT0/1-

RI PT

carcinomas which have resulted from more advanced primary tumors show clearly worse outcome. After NT the UICC-pTNM-staging-system for EAC provides adequate prognostication, at least for patients with advanced tumor stage. The AJCC-ypTNM-staging-system for EAC can be confirmed for

SC

prediction of prognosis, and should be preferred over the UICC-pTNM-staging after NT because of inclusion of ypT0.

M AN U

For GC both the UICC-pTNM- and the AJCC-ypTNM-staging-system do not sufficiently stratify patients according to prognosis, and both systems do not classify patients without residual tumor. The staging systems for neoadjuvantly treated GC should be revised. Evaluation and data-driven development of an adequate ypTNM-staging-system in a large population of GC patients who

TE D

received NT analogous to WECC-data is much needed.

A simplified staging-system might be more adequate for prognostication of patients after neoadjuvant

AC C

EP

therapy.

17

ACCEPTED MANUSCRIPT

Acknowledgements: Leila Sisic was sponsored by the University of Heidelberg medical faculty in the context of a research scholarship. This funding had no involvement in study design; in collection, analysis, or interpretation

RI PT

of data; in writing of the report; and in the decision to submit the article.

SC

Conflict of interest:

The authors declare that they do not have any commercial interest in the subject of study.

M AN U

GM Haag reports fees for advisory role from Sanofi, Roche, Taiho, Nordic, Lilly, Pfizer, honoraria from Roche, travel grants from Amgen, Ipsen and Celgene; research funding is provided by Nordic

AC C

EP

TE D

and Taiho Pharmaceuticals. There is no relationship to the submitted work.

18

ACCEPTED MANUSCRIPT Titles and legends to figures

Figure 1: Prognostic value of pathological T- and N-category.

RI PT

Kaplan-Meier plots for overall survival according to a) pT-category, b) pN-category, c) ypT-category, and d) ypN-category.

SC

Figure 2: Prognostic value of UICC-pTNM- and AJCC-ypTNM-staging-sytem.

M AN U

Kaplan-Meier plots for overall survival after primary surgery according to UICC-pTNM-stage in a) esophageal and b) gastric adenocarcinoma; Kaplan-Meier plots for overall survival after neoadjuvant treatment according to UICC-pTNM-stage in c) esophageal and d) gastric adenocarcinoma and

TE D

according to e) AJCC-ypTNM-stage in esophageal adenocarcinoma.

Figure 3: Prognostic value of proposed staging system. Kaplan-Meier plots for overall survival according to proposed simplified staging system after

AC C

EP

neoadjuvant treatment for a) esophageal and b) gastric adenocarcinoma.

19

ACCEPTED MANUSCRIPT References:

AC C

EP

TE D

M AN U

SC

RI PT

[1] Washington K. 7th edition of the AJCC cancer staging manual: stomach. Annals of surgical oncology. 2010;17(12):3077-9. Epub 2010/10/01. doi: 10.1245/s10434-010-1362-z. PubMed PMID: 20882416. [2] Ahn HS, Lee HJ, Hahn S, Kim WH, Lee KU, Sano T, et al. Evaluation of the seventh American Joint Committee on Cancer/International Union Against Cancer Classification of gastric adenocarcinoma in comparison with the sixth classification. Cancer. 2010;116(24):5592-8. Epub 2010/08/26. doi: 10.1002/cncr.25550. PubMed PMID: 20737569. [3] Rice TW, Rusch VW, Apperson-Hansen C, Allen MS, Chen LQ, Hunter JG, et al. Worldwide esophageal cancer collaboration. Dis Esophagus. 2009;22(1):1-8. PubMed PMID: 19196264. [4] Wilke H, Lordick F, Meyer HJ, Stahl M. (Neo)-adjuvant chemo(-radio) therapy for adenocarcinomas of the gastroesophageal junction and the stomach in the West. Digestive surgery. 2013;30(2):112-8. Epub 2013/07/23. doi: 10.1159/000350935. PubMed PMID: 23867587. [5] Nomura M, Shitara K, Kodaira T, Hatooka S, Mizota A, Kondoh C, et al. Prognostic impact of the 6th and 7th American Joint Committee on Cancer TNM staging systems on esophageal cancer patients treated with chemoradiotherapy. International journal of radiation oncology, biology, physics. 2012;82(2):946-52. Epub 2011/03/03. doi: 10.1016/j.ijrobp.2010.12.045. PubMed PMID: 21362578. [6] Kim JY, Nelson RA, Kim J, Raz D. How well does pathologic stage predict survival for esophageal adenocarcinoma after neoadjuvant therapy? Journal of thoracic disease. 2015;7(4):7349. Epub 2015/05/15. doi: 10.3978/j.issn.2072-1439.2015.04.30. PubMed PMID: 25973240; PubMed Central PMCID: PMC4419330. [7] Mehta SP, Jose P, Mirza A, Pritchard SA, Hayden JD, Grabsch HI. Comparison of the prognostic value of the 6th and 7th editions of the Union for International Cancer Control TNM staging system in patients with lower esophageal cancer undergoing neoadjuvant chemotherapy followed by surgery. Dis Esophagus. 2013;26(2):182-8. Epub 2012/05/18. doi: 10.1111/j.14422050.2012.01350.x. PubMed PMID: 22591020. [8] Rizk NP, Venkatraman E, Bains MS, Park B, Flores R, Tang L, et al. American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma. J Clin Oncol. 2007;25(5):507-12. Epub 2007/02/10. doi: 10.1200/JCO.2006.08.0101. PubMed PMID: 17290058. [9] Shapiro J, van Klaveren D, Lagarde SM, Toxopeus EL, van der Gaast A, Hulshof MC, et al. Prediction of survival in patients with oesophageal or junctional cancer receiving neoadjuvant chemoradiotherapy and surgery. The British journal of surgery. 2016;103(8):1039-47. Epub 2016/04/27. doi: 10.1002/bjs.10142. PubMed PMID: 27115731. [10] Brierley J, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. Eighth edition ed. Chichester, West Sussex, UK ; Hoboken, NJ: John Wiley & Sons, Inc; 2017. [11] Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC cancer staging manual. Eighth edition ed. [Cham]: Springer; 2017. [12] Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Apperson-Hansen C, Blackstone EH, et al. Recommendations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016;29(8):906-12. Epub 2016/12/03. doi: 10.1111/dote.12538. PubMed PMID: 27905170; PubMed Central PMCID: PMC5137813. [13] Rice TW, Lerut TE, Orringer MB, Chen LQ, Hofstetter WL, Smithers BM, et al. Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data. Dis Esophagus. 2016;29(7):715-23. Epub 2016/10/13. doi: 10.1111/dote.12513. PubMed PMID: 27731548. [14] Sano T, Coit DG, Kim HH, Roviello F, Kassab P, Wittekind C, et al. Proposal of a new stage grouping of gastric cancer for TNM classification: International Gastric Cancer Association staging project. Gastric cancer : official journal of the International Gastric Cancer Association and the

20

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Japanese Gastric Cancer Association. 2017;20(2):217-25. Epub 2016/02/22. doi: 10.1007/s10120016-0601-9. PubMed PMID: 26897166; PubMed Central PMCID: PMC4992472. [15] Blank S, Schmidt T, Heger P, Strowitzki MJ, Sisic L, Heger U, et al. Surgical strategies in true adenocarcinoma of the esophagogastric junction (AEG II): thoracoabdominal or abdominal approach? Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2017. Epub 2017/07/08. doi: 10.1007/s10120-017-0746-1. PubMed PMID: 28685209. [16] Sisic L, Blank S, Nienhuser H, Haag GM, Jager D, Bruckner T, et al. The postoperative part of perioperative chemotherapy fails to provide a survival benefit in completely resected esophagogastric adenocarcinoma. Surgical oncology. 2017. Epub 2017/07/08. doi: 10.1016/j.suronc.2017.06.001. PubMed PMID: 28684226. [17] Sisic L, Strowitzki MJ, Blank S, Nienhueser H, Dorr S, Haag GM, et al. Postoperative follow-up programs improve survival in curatively resected gastric and junctional cancer patients: a propensity score matched analysis. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2017. doi: 10.1007/s10120-017-0751-4. PubMed PMID: 28741059. [18] Langer R, Becker K, Zlobec I, Gertler R, Sisic L, Buchler M, et al. A multifactorial histopathologic score for the prediction of prognosis of resected esophageal adenocarcinomas after neoadjuvant chemotherapy. Annals of surgical oncology. 2014;21(3):915-21. Epub 2013/11/28. doi: 10.1245/s10434-013-3410-y. PubMed PMID: 24281419. [19] Gaca JG, Petersen RP, Peterson BL, Harpole DH, Jr., D'Amico TA, Pappas TN, et al. Pathologic nodal status predicts disease-free survival after neoadjuvant chemoradiation for gastroesophageal junction carcinoma. Annals of surgical oncology. 2006;13(3):340-6. Epub 2006/02/18. doi: 10.1245/ASO.2006.02.023. PubMed PMID: 16485154. [20] Gu Y, Swisher SG, Ajani JA, Correa AM, Hofstetter WL, Liao Z, et al. The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer. 2006;106(5):1017-25. Epub 2006/02/04. doi: 10.1002/cncr.21693. PubMed PMID: 16456809. [21] Holscher AH, Drebber U, Schmidt H, Bollschweiler E. Prognostic classification of histopathologic response to neoadjuvant therapy in esophageal adenocarcinoma. Annals of surgery. 2014;260(5):779-84; discussion 84-5. Epub 2014/11/08. doi: 10.1097/SLA.0000000000000964. PubMed PMID: 25379849. [22] Reynolds JV, Muldoon C, Hollywood D, Ravi N, Rowley S, O'Byrne K, et al. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Annals of surgery. 2007;245(5):707-16. Epub 2007/04/26. doi: 10.1097/01.sla.0000254367.15810.38. PubMed PMID: 17457163; PubMed Central PMCID: PMC1877071. [23] Law S, Kwong DL, Wong KH, Kwok KF, Wong J. The effects of neoadjuvant chemoradiation on pTNM staging and its prognostic significance in esophageal cancer. J Gastrointest Surg. 2006;10(9):1301-11. Epub 2006/11/23. doi: 10.1016/j.gassur.2006.06.009. PubMed PMID: 17114016. [24] Ott K, Blank S, Becker K, Langer R, Weichert W, Roth W, et al. Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10 % residual tumor. Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie. 2013;398(2):239-49. Epub 2012/12/28. doi: 10.1007/s00423-012-1039-0. PubMed PMID: 23269519. [25] Schmidt T, Sicic L, Blank S, Becker K, Weichert W, Bruckner T, et al. Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas. British journal of cancer. 2014;110(7):1712-20. Epub 2014/02/27. doi: 10.1038/bjc.2014.94. PubMed PMID: 24569472; PubMed Central PMCID: PMC3974097. [26] Davies AR, Gossage JA, Zylstra J, Mattsson F, Lagergren J, Maisey N, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol. 2014;32(27):2983-90. Epub 2014/07/30. doi: 10.1200/JCO.2014.55.9070. PubMed PMID: 25071104.

21

ACCEPTED MANUSCRIPT

SC

RI PT

[27] Pennathur A, Luketich JD, Landreneau RJ, Ward J, Christie NA, Gibson MK, et al. Long-term results of a phase II trial of neoadjuvant chemotherapy followed by esophagectomy for locally advanced esophageal neoplasm. The Annals of thoracic surgery. 2008;85(6):1930-6; discussion 6-7. Epub 2008/05/24. doi: 10.1016/j.athoracsur.2008.01.097. PubMed PMID: 18498797. [28] Korst RJ, Kansler AL, Port JL, Lee PC, Kerem Y, Altorki NK. Downstaging of T or N predicts longterm survival after preoperative chemotherapy and radical resection for esophageal carcinoma. The Annals of thoracic surgery. 2006;82(2):480-4; discussion 4-5. Epub 2006/07/26. doi: 10.1016/j.athoracsur.2006.03.072. PubMed PMID: 16863749. [29] Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J, et al. Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Annals of surgery. 2011;253(5):934-9. Epub 2011/04/15. doi: 10.1097/SLA.0b013e318216f449. PubMed PMID: 21490451. [30] Langer R, Ott K, Feith M, Lordick F, Siewert JR, Becker K. Prognostic significance of histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. Mod Pathol. 2009;22(12):1555-63. Epub 2009/10/06. doi: modpathol2009123 [pii]

AC C

EP

TE D

M AN U

10.1038/modpathol.2009.123. PubMed PMID: 19801967. [31] Ajani JA, Mansfield PF, Crane CH, Wu TT, Lunagomez S, Lynch PM, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol. 2005;23(6):1237-44. Epub 2005/02/19. doi: 10.1200/JCO.2005.01.305. PubMed PMID: 15718321. [32] Barbour AP, Jones M, Gonen M, Gotley DC, Thomas J, Thomson DB, et al. Refining esophageal cancer staging after neoadjuvant therapy: importance of treatment response. Annals of surgical oncology. 2008;15(10):2894-902. Epub 2008/07/30. doi: 10.1245/s10434-008-0084-y. PubMed PMID: 18663531. [33] Meredith KL, Weber JM, Turaga KK, Siegel EM, McLoughlin J, Hoffe S, et al. Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer. Annals of surgical oncology. 2010;17(4):1159-67. Epub 2010/02/09. doi: 10.1245/s10434009-0862-1. PubMed PMID: 20140529. [34] Swisher SG, Hofstetter W, Wu TT, Correa AM, Ajani JA, Komaki RR, et al. Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT). Annals of surgery. 2005;241(5):810-7; discussion 7-20. Epub 2005/04/26. doi: 00000658-200505000-00015 [pii]. PubMed PMID: 15849517. [35] Vallbohmer D, Holscher AH, DeMeester S, DeMeester T, Salo J, Peters J, et al. A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer. Annals of surgery. 2010;252(5):744-9. Epub 2010/11/03. doi: 10.1097/SLA.0b013e3181fb8dde. PubMed PMID: 21037429. [36] Smyth EC, Fassan M, Cunningham D, Allum WH, Okines AF, Lampis A, et al. Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. J Clin Oncol. 2016;34(23):2721-7. Epub 2016/06/15. doi: 10.1200/JCO.2015.65.7692. PubMed PMID: 27298411; PubMed Central PMCID: PMC5019747 online at www.jco.org. Author contributions are found at the end of this article. [37] van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. The New England journal of medicine. 2012;366(22):2074-84. Epub 2012/06/01. doi: 10.1056/NEJMoa1112088. PubMed PMID: 22646630. [38] Schulz C, Kullmann F, Kunzmann V, Fuchs M, Geissler M, Vehling-Kaiser U, et al. NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors. International journal of cancer. 2015;137(3):678-85. Epub 2014/12/23. doi: 10.1002/ijc.29403. PubMed PMID: 25530271. [39] Springfeld C, Wiecha C, Kunzmann R, Heger U, Weichert W, Langer R, et al. Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in

22

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Patients with Esophagogastric Adenocarcinoma. Annals of surgical oncology. 2015;22 Suppl 3:S90514. Epub 2015/05/24. doi: 10.1245/s10434-015-4617-x. PubMed PMID: 26001861. [40] Ikoma N, Blum M, Estrella JS, Das P, Hofstetter WL, Fournier KF, et al. Evaluation of the American Joint Committee on Cancer 8th edition staging system for gastric cancer patients after preoperative therapy. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2017. Epub 2017/06/24. doi: 10.1007/s10120-0170743-4. PubMed PMID: 28643144. [41] Reim D, Gertler R, Novotny A, Becker K, zum Buschenfelde CM, Ebert M, et al. Adenocarcinomas of the esophagogastric junction are more likely to respond to preoperative chemotherapy than distal gastric cancer. Annals of surgical oncology. 2012;19(7):2108-18. Epub 2011/12/02. doi: 10.1245/s10434-011-2147-8. PubMed PMID: 22130620. [42] Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. The lancet oncology. 2016;17(12):1697-708. Epub 2016/10/26. doi: 10.1016/S1470-2045(16)30531-9. PubMed PMID: 27776843.

ACCEPTED MANUSCRIPT Table 1: Baseline characteristic of patients after primary surgery and neoadjuvant treatment in a) esophageal adenocarcinoma and b) gastric adenocarcinoma NT (n=190) n %

Total (n=363)

12 105 56

6.9% 60.7% 32.4%

10 140 40

5.3% 73.7% 21.1%

22 245 96

136 37

78.6% 21.4%

169 21

88.9% 11.1%

95 95

79 81 13

45.7% 46.8% 7.5%

67 106 17

98 44 31 18 44 102 3 6 121 47 5

56.6% 25.4% 17.9%

10.4% 25.4% 59.0% 1.7% 3.5% 69.9% 27.2% 2.9%

NA NA NA

EP

AC C

50.0% 50.0%

102 39 49

35.3% 55.8% 8.9%

53.7% 20.5% 25.8%

6.1% 67.5% 26.4%

RI PT

41.6% 58.4%

p-value 0.029

305 58 167 196

SC

72 101

TE D

Age at diagnosis ≤45 years 46-69 years ≥70 years Sex Male Female Localization AEG I AEG II Grading Low grade (G1/2) High grade (G3/4) Missing data Laurén classification Intestinal Non-intestinal Missing data cT-category cT1 cT2 cT3 cT4 Missing data cN-category cN0 cN+ Missing data Type of neoadjuvant treatment Chemotherapy Chemoradiotherapy Radiotherapy Surgical procedure THG Ivor Lewis procedure Other (y)pT-category (y)pT0 (y)pT1a (y)pT1b (y)pT2 (y)pT3 (y)pT4a (y)pT4b (y)pN-category (y)pN0 (y)pN1 (y)pN2 (y)pN3 R-category

PS (n=173) n %

M AN U

a) Esophageal AC (n=363)

146 187 30

200 83 89

0.007

84.0% 16.0%

0.110

46.0% 54.0%

0.051

40.2% 51.5% 8.3% 0.539 55.1% 22.9% 22.0% <0.001

3 16 151 17 3

1.6% 8.4% 79.5% 8.9% 1.6%

21 60 253 20 9

5.8% 16.5% 69.7% 5.5% 2.5%

34 153 3

17.9% 80.5% 1.6%

155 200 8

42.7% 55.1% 2.2%

<0.001

NA 172 12 5

90.5% 6.3% 2.6%

172 12 5

47.4% 3.3% 1.4% 0.002

82 75 16

47.4% 43.4% 9.2%

64 117 9

33.7% 61.6% 4.7%

146 192 25

40.2% 52.9% 6.9%

0 14 19 35 85 18 2

0.0% 8.1% 11.0% 20.2% 49.1% 10.4% 1.2%

26 1 12 27 111 12 1

13.7% 0.5% 6.3% 14.2% 58.4% 6.3% 0.5%

26 15 31 62 196 30 3

7.2% 4.1% 8.5% 17.1% 54.0% 8.3% 0.8%

<0.001

0.045 63 29 31 40

36.4% 16.8% 17.9% 23.1%

89 39 27 28

46.8% 20.5% 14.2% 14.7%

152 68 58 68

41.9% 18.7% 16.0% 18.7% 0.224

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

R0 146 84.4% 169 88.9% 315 86.8% Rx 6 3.5% 2 1.1% 8 2.2% R1 21 12.1% 19 10.0% 40 11.0% UICC pTNM Stage <0.001 T0 N any 0 0.0% 26 13.7% 26 7.2% IA 14 8.1% 0 0.0% 14 3.9% IB 15 8.7% 11 5.8% 26 7.2% IIA 15 8.7% 19 10.0% 34 9.4% IIB 3 1.7% 1 0.5% 4 1.1% IIIA 26 15.0% 43 22.6% 69 19.0% IIIB 47 27.2% 53 27.9% 100 27.5% IVA 53 30.6% 37 19.5% 90 24.8% AJCC ypTNM Stage NA I NA 52 27.4% 52 14.3% II NA 34 17.9% 34 9.4% IIIA 9 4.7% 9 2.5% NA IIIB NA 57 30.0% 57 15.7% IVA NA 38 20.0% 38 10.5% Adjuvant treatment <0.001 Not administered 125 72.3% 92 48.4% 217 59.8% Administered 48 27.7% 98 51.6% 146 40.2% Type of adjuvant treatment <0.001 Chemotherapy 26 15.0% 86 45.3% 112 30.9% Chemoradiotherapy 11.0% 12 6.3% 31 8.5% 19 Radiotherapy 1.2% 0 0.0% 2 0.6% 2 AC = adenocarcinoma; PS = primary surgery; NT= neoadjuvant treatment; AEG = adenocarcinoma of the esophago-gastric junction; NA= not applicable; THG = transhiatal extended gastrectomy; values in bold print indicate a significance-level of p≤0.05

ACCEPTED MANUSCRIPT PS (n=223) n %

Total (n=377) p-value 0.013

6.7% 53.4% 39.9%

20 92 42

13.0% 59.7% 27.3%

35 211 131

9.3% 56.0% 34.7%

144 79

64.6% 35.4%

100 54

64.9% 35.1%

244 133

64.7% 35.3%

13 210

5.8% 94.2%

33 121

21.4% 78.6%

65 144 14

29.1% 64.6% 6.3%

29 106 19

18.8% 68.8% 12.3%

98 119 6

43.9% 53.4% 2.7%

67 78 9

0.943

51 106 51 11 4 160 59 4

RI PT

<0.001

12.2% 87.8%

94 250 33

24.9% 66.3% 8.8%

SC

46 331

43.5% 50.6% 5.8%

43.8% 52.3% 4.0% <0.001

0 9 107 36 2

0.0% 5.8% 69.5% 23.4% 1.3%

51 115 158 47 6

13.5% 30.5% 41.9% 12.5% 1.6%

71.7% 26.5% 1.8%

32 121 1

20.8% 78.6% 0.6%

192 180 5

50.9% 47.7% 1.3%

154 0 0

100.0% 0.0% 0.0%

154 0 0

40.8% 0.0% 0.0%

122 86 11 NA 4

54.7% 38.6% 4.9%

0.051

0.845

165 197 15

22.9% 47.5% 22.9% 4.9% 1.8%

NA NA NA

<0.001

NA

<0.001 29.2% 48.1% 20.8%

1.8%

45 74 32 NA 3

0 32 46 33 89 16 7

0.0% 14.3% 20.6% 14.8% 39.9% 7.2% 3.1%

109 37 42 22 13

48.9% 16.6% 18.8% 9.9% 5.8%

EP

AC C

NT (n=154) %

15 119 89

TE D

Age at diagnosis ≤45 years 46-69 years ≥70 years Sex Male Female Localization AEG III Gastric cancer Grading Low grade (G1/2) High grade (G3/4) Missing data Laurén classification Intestinal Non-intestinal Missing data cT-category cT1 cT2 cT3 cT4 Missing data cN-category cN0 cN+ Missing data Type of neoadjuvant treatment Chemotherapy Chemoradiotherapy Radiotherapy Surgical procedure Subtotal gastrectomy Total gastrectomy THG Ivor Lewis procedure Other (y)pT-category (y)pT0 (y)pT1a (y)pT1b (y)pT2 (y)pT3 (y)pT4a (y)pT4b (y)pN-category (y)pN0 (y)pN1 (y)pN2 (y)pN3a (y)pN3b R-category

n

M AN U

b) Gastric AC (n=377)

44.3% 42.4% 11.4%

1.9%

167 160 43 NA 7

8 6 13 19 82 15 11

5.2% 3.9% 8.4% 12.3% 53.2% 9.7% 7.1%

8 38 59 52 171 31 18

2.1% 10.1% 15.6% 13.8% 45.4% 8.2% 4.8%

68 27 20 27 12

44.2% 17.5% 13.0% 17.5% 7.8%

177 64 62 49 25

46.9% 17.0% 16.4% 13.0% 6.6%

1.9% <0.001

0.135

0.835

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

R0 201 90.1% 136 88.3% 337 89.4% Rx 8 3.6% 6 3.9% 14 3.7% R1 14 6.3% 12 7.8% 26 6.9% UICC pTNM Stage <0.001 T0 N0 0 0.0% 8 5.2% 8 2.1% IA 59 26.5% 14 9.1% 14 3.7% IB 28 12.6% 14 9.1% 14 3.7% IIA 40 17.9% 30 19.5% 30 8.0% IIB 30 13.5% 27 17.5% 27 7.2% IIIA 31 13.9% 22 14.3% 22 5.8% IIIB 20 9.0% 27 17.5% 27 7.2% IIIC 15 6.7% 12 7.8% 12 3.2% AJCC ypTNM Stage NA T0 N0 NA 8 5.2% 8 2.1% I NA 28 18.2% 28 7.4% II 57 37.0% 57 15.1% NA III NA 61 39.6% 61 16.2% Adjuvant treatment <0.001 Not administered 175 78.5% 44 28.6% 219 58.1% Administered 48 21.5% 110 71.4% 158 41.9% Type of adjuvant treatment <0.001 Chemotherapy 13.9% 44 28.6% 75 19.9% 31 Chemoradiotherapy 16 7.2% 96 62.3% 112 29.7% Radiotherapy 0.4% 0 0.0% 1 0.3% 1 AC = adenocarcinoma; PS = primary surgery; NT= neoadjuvant treatment; AEG = adenocarcinoma of the esophago-gastric junction; NA= not applicable; THG = transhiatal extended gastrectomy; values in bold print indicate a significance-level of p≤0.05

ACCEPTED MANUSCRIPT Table 2: Overall survival according to a) pathological TN-category and according to UICC-pTNM-. AJCC-ypTNM-. and proposed simplified staging system in b) esophageal and c) gastric adenocarcinoma

n

17 n.r. 33 103.8 65.6 - 142.1 107 37.5 27.5 - 47.6 25 22.9 17.2 - 28.6

172 66 73 85 n

43 n.r. 26 123.6 73.4 - 173.9 43 38.4 0.0 - 80.6 70 19.5 15.9 - 23.2 PS (n=173) 95%CI † mOS

0 29 14 15 18 15 3 73 26 47 53

4 2 2 6 6 0 46 13 33 45

UICC pTNM Stage T0 N0 Stage I IA IB Stage II IIA IIB Stage III IIIA IIIB

p <0.001

n

46.5 150.7 43.6 21.5

NA NA NA

SC

42 120.1 34 39.3 24.9 - 53.7 23 37.7 25.0 - 50.4 49 26.4 19.0 - 33.8 NT (n=190) † mOS 95%CI

n

-

PS (n=223) mOS 95%CI

n



0 87 59 28 70 40 30 66 31 20

13 n.r. 7 n.r. 6 n.r. 25 113.7 113.7 78.9 - 148.6 15 10 103.8 43 28.4 14.6 - 42.1 16 51.7 12 29.7 11.4 - 48.0

26 11 0 11 20 19 1 96 43 53 37

8 6

97.2 54.9

0.0 0.0 19.1 5.5 18.1 -

6 2 1 1 43 16 27 25

54.9 n.r. n.r. 14.1 57.0 78.2 29.1 23.1

52 34 66 9 57 38

13 120.1 11 78.2 34 34.9 15.4 - 54.3 5 34.9 10.6 - 59.1 29 38.5 15.2 - 61.8 26 22.6 18.3 - 26.9

130.3

94.9 52.8 28.1 <0.001

NA

p <0.001

p <0.001

130.3

NA

-

NA NA NA NA NA NA

<0.001

157 66 47 74

M AN U

30.4 20.6 14.2 15.7

-

TE D

n.r. n.r. n.r. 149.6 149.6 n.r. 38.4 85.6 28.9 18.6

p 0.002

12 97.2 39.5 - 154.8 10 120.1 13 n.r. 90 52.1 30.2 - 74.0 23 22.3 10.6 - 34.0

34 32 46 193 39

p <0.001

NT (n=344) mOS 95%CI



<0.001

AC C

UICC pTNM Stage T0 N any Stage I IA IB Stage II IIA IIB Stage III IIIA IIIB Stage IVA AJCC ypTNM Stage Stage I Stage II Stage III IIIA IIIB Stage IVA Proposed Stage Stage I Stage II Stage III c) Gastric AC

NA 111 68 174 43

EP

(y)pT-category (y)pT0 (y)pT1 (y)pT2 (y)pT3 (y)pT4 (y)pN-category (y)pN0 (y)pN1 (y)pN2 (y)pN3 b) Esophageal AC

PS (n=396) mOS 95%CI



RI PT

a) All patients

<0.001 86 24 120.1 66 34 34.9 15.4 - 54.3 38 26 22.6 18.3 - 26.9 NT (n=154) n † mOS 95%CI 8 28 14 14 57 30 27 61 22 27

4 5 1 4 14 6 8 41 15 20

56.8 n.r. n.r. 39.5 92.1 84.9 92.1 30.1 34.8 26.4

12.0 - 101.6 20.6 - 39.5 27.2 - 42.4 9.1 - 43.7

p <0.001

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

IIIC 15 15 12.2 8.4 - 16.0 12 6 29.7 3.2 - 56.2 AJCC ypTNM Stage NA <0.001 T0 N0 NA 8 4 56.8 12.0 - 101.6 Stage I 28 5 n.r. NA Stage II NA 57 14 92.1 Stage III NA 61 41 30.1 20.6 - 39.5 Proposed Stage NA <0.001 Stage I NA 59 13 n.r. Stage II NA 46 18 92.1 17.3 - 166.9 Stage III NA 49 33 29.6 19.1 - 40.0 AC= adenocarcinoma; PS= primary surgery; NT= neoadjuvant treatment; †= deaths; mOS= median overall survival; CI = confidence interval; n.r.= not reached; NA= not applicable; values in bold print indicate a significance-level of p≤0.05

ACCEPTED MANUSCRIPT Table 3: Proposed simplified pathologic staging system for esophageal and gastric adenocarcinoma after neoadjuvant treatment ypN N0 N1-2 N0 N1-2 N0-2 N3

ypT T0-3 T0-3 T4a T4a T4b any

AC C

EP

TE D

M AN U

SC

III

RI PT

Stage I II

ACCEPTED MANUSCRIPT Figure 1: Prognostic value of pathological T- and N-category. Kaplan-Meier plots for overall survival according to a) pT-category, b) pN-category, c) ypT-category, and d) ypN-category. b)

c)

d)

AC C

EP

TE D

M AN U

SC

RI PT

a)

ACCEPTED MANUSCRIPT Figure 2: Prognostic value of UICC-pTNM- and AJCC-ypTNM-staging-system. Kaplan-Meier plots for overall survival after primary surgery according to UICC-pTNM-stage in a) esophageal and b) gastric adenocarcinoma; Kaplan-Meier plots for overall survival after neoadjuvant treatment according to UICCpTNM-stage in c) esophageal and d) gastric adenocarcinoma and according to e) AJCC-ypTNM-stage in esophageal adenocarcinoma. b)

M AN U

SC

RI PT

a)

d)

AC C

e)

EP

TE D

c)

ACCEPTED MANUSCRIPT Figure 3: Prognostic value of proposed staging system. Kaplan-Meier plots for overall survival according to proposed simplified staging system after neoadjuvant treatment for a) esophageal and b) gastric adenocarcinoma. b)

AC C

EP

TE D

M AN U

SC

RI PT

a)