U n i v e r s i t y o f G r o n i n g e n ,

F a c u l t y o f M e d i c a l

s c i e n c e s

H o m e a d d r e s s :

H o o r n s e d i e p 1 2 8

9 7 2 5 H N G r o n i n g e n

S t u d e n t n u m b e r :

1 8 2 6 0 8 5

[ G e e f h e t f a x n u m m e r

o p ]

2 9 - 5 - 2 0 1 5

H.E.M. (Hiske) de Boer

Supervisor: Prof. Dr. J.T.M. Plukker

Department of Surgical Oncology

University of Groningen

University Medical Center Groningen

The preoperative work-up of patients with esophageal cancer: What is the value of endoscopic ultrasonograpy (EUS) after PET/CT?

2

Abstract (English)

Background: The optimal staging sequence in esophageal cancer patients is still debatable.

Positron emission tomography/computed tomography (PET/CT) and endoscopic ultrasonography

(EUS) are used in a non-specific order. Most European countries perform EUS first followed by

CT or PET/CT, whereas it is just the reverse in the US. Moreover the need for an invasive EUS

method remains unknown. This retrospective study assessed the additional value of EUS after

PET/CT and the influence or benefit of EUS on the treatment decision making and if patients

could be selected for EUS based on PET/CT (EUS on demand).

Patients and Method: All symptomatic esophageal cancer patients (T1-4a,N0-3M0), diagnosed

between 2009 and 2015 at the University Medical Centre Groningen, were eligible for analysis.

The primary outcome was the additional value of EUS after PET/CT, defined as lymph node (LN)

up/down staging, metastasis outside of the locoregional area, and additional information on

curability (T4b and M+). We also assessed how often EUS had influenced the treatment:

including a possible change of the radiation area (tumor target volumes), the resectability (T4b),

or detected distant metastasis. In addition, we defined when EUS should be made, based on the

PET/CT, and assessed if we could select patients that would benefit from EUS.

Results: A total of 299 patients were eligible for inclusion, of whom 62.5% had a complete EUS,

19.1% an incomplete, and 18.4% did not receive an EUS. EUS after PET/CT gave additional

information in 169 patients (69.3%) and changed the treatment plan in 69 patients (28%). We

found that patients with an EUS significantly (P<0.001) more often had a useful EUS, according

to the above mentioned definition of a valuable EUS. However, using this definition we would

have missed 31 patients (14.9%) who seemed to benefit from EUS.

Conclusion: Although EUS gave additional information after PET/CT in most cases, it only

changed the treatment after PET/CT in 28 % of the patients. We were able to select patients,

based on the PET/CT, that would benefit from EUS. However, this definition should be optimized

to become applicable in all patients with esophageal cancer.

Abstract (Dutch)

Achtergrond De optimale volgorde van stagering bij patiënten met oesofaguskanker staat ter

discussie. Positron emission tomography/computed tomography (PET/CT) en endoscopische

ultrasonography (EUS) worden vaak in willekeurige volgorde gebruikt. De meeste Europese

landen doen eerst een EUS gevolgd door CT of PET/CT, terwijl dit in de USA juist andersom is.

Daarnaast staat het nut van deze invasieve EUS ter discussie. Deze retrospectieve studie

onderzocht de additionele waarde van EUS na PET/CT en de invloed of bijdrage van EUS op het

kiezen van de behandeling en of we patiënten konden selecteren voor EUS, gebaseerd op de up-

front PET/CT (EUS op indicatie).

Patiënten en Methode Alle symptomatische oesofaguskanker patiënten (T1-4a, N0-3M0)

gediagnosticeerd tussen 2009 en 2015 in het Universitair Medisch Centrum Groningen, kwamen

in aanmerking voor analyse. De primaire uitkomst was de additionele waarde van EUS na

PET/CT, gedefinieerd als lymfeklier (LN) up/downstaging, LN metastasen op locaties buiten het

locoregionale gebied en additionele informatie over de incurabiliteit (T4b en M+). Vervolgens

keken we hoe vaak EUS de behandeling beïnvloedde: EUS had invloed als het radiatiegebied

veranderde, de resectabiliteit veranderde, of afstandsmetastasen vond. Verder definieerden we

wanneer een EUS nodig was op basis van de PET/CT, en of we hiermee patiënten konden

selecteren voor een zinvolle EUS.

Resultaten In totaal werden 299 patiënten geïncludeerd, waarvan 62,5% een complete, 19.1% een

incomplete, en 18.4% geen EUS kregen. EUS na PET/CT gaf additionele informatie in 169

patiënten (69.3%) en veranderde de behandeling in 69 patiënten (28%). We vonden dat de groep

die volgens onze definitie een EUS moest krijgen, significant (P<0.001) vaker een zinvolle EUS

hadden. Niettemin, miste onze definitie 31 patiënten (14.9%) welke een voordeel zouden kunnen

hebben gehad van de EUS.

Conclusie Hoewel EUS additionele informatie oplevert na PET/CT, beïnvloedde EUS de

behandeling maar in 28% van de patiënten. We zijn er in geslaagd om patiënten te selecteren die

op basis van de PET/CT, profijt hebben na EUS. Echter, de selectie moet verder worden

geoptimaliseerd om in de toekomst toepasbaar te zijn voor alle patiënten met oesofaguskanker.

3

Index

Abstracts (English and Dutch) 2

1. Background 4 - 9

1.1. Treatment of esophageal cancer

1.1.1. Curative treatment options

1.1.2. Palliative treatment options

1.2. Staging of esophageal cancer

1.2.1. Computed tomography (CT)

1.2.2. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT)

1.2.3. Endoscopic ultrasonography (EUS)

1.3. Purpose of the study

2. Research questions 9

3. Patients and Methods 10 - 13

3.1. Patients

3.2. Methods

3.3. Staging

3.3.1. Endoscopic ultrasonography (EUS)

3.3.2. Computed tomography (CT)

3.3.3. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT)

3.4. Treatment

3.5. Statistical analysis

4. Results 14 - 17

4.1. Study population

4.2. Additional value of EUS after PET/CT

4.3. Influence of EUS on treatment after PET/CT

4.4. Designing a definition to predict whether EUS is necessary

5. Discussion 18- 21

6. Acknowledgements 21

7. List of abbreviations 21

8. References 22-25

Appendix 1 26-27

4

1. Background

Esophageal cancer is the eight most commonly diagnosed malignant tumor worldwide and the

sixth most common cause of cancer-related death in the world.(1) The two main

histopathologic types of esophageal cancer (EC) are adenocarcinoma (AC) and squamous cell

carcinoma (SCC). Other less common EC types are small cell carcinoma, carcinosarcomas

and melanoma. Over the past few years the incidence of EC rose rapidly in western countries

(eg. France, the Netherlands, UK, USA and Australia). The main cause of the higher

incidence of EC is an increase of AC. Its incidence is exceeding the incidence of SCC in

several western countries, whereas SCC remains stable or even declines.(2,3) In the

Netherlands the incidence of EC increased from 920 male patients in 1989 to 2032 patients in

2003, an increase of 220%.(3) In addition, EC has a very poor prognosis with a 5-year overall

survival (OS) rate of 15 % in the Netherlands between 2003 and 2007.(4) Currently, the

global 5-year OS rate ranges from 15-25% .(1) However, the OS rate is relatively higher (25-

35%) in patients who can be treated curatively with surgery alone, and even increases up to

47% after a trimodality treatment, including neoadjuvant chemoradiotherapy (nCRT)followed

by surgery.(5) Although the overall outcome is relatively lower, patients who are medically

unfit can still be treated with curative intent by definitive chemoradiotherapy (dCRT) or

radiotherapy (dRT).

All new patients with esophageal cancer are staged according to the 7th TNM classification of

the American Joint Committee on Cancer (AJCC) (Appendix 1).(6) Accurate staging is

essential and has a huge impact on the therapeutic outcome, which can be either curative or

palliative. Currently, the optimal staging sequence remains debatable. Staging techniques

such as endoscopic ultrasonography (EUS), computed tomography (CT) and 18F-

fluorodeoxy-glucose positron emission tomography (FDG-PET) are used at different

moments in the preoperative staging of EC. Most European countries perform EUS first

followed by CT or PET/CT, whereas it is just the reverse in the US. Moreover the need for an

invasive EUS method remains unknown. Recently a research group found that PET/CT more

than EUS is a predictor of curative resectability.(7) However, the additional value of each

staging technique on the optimal treatment planning, especially EUS, has not yet been

assessed.

1.1 Treatment of esophageal cancer

Curative treatment of EC is only applicable in patients without distant metastatic disease (M0)

and without extension of the primary tumor into adjacent vital structures (T1-T4a). The

median survival rate of patients undergoing surgery with curative intent is 20.3 months

whereas the median survival rate for patients with metastatic disease who were treated with

palliative intent is only 6 months.(8,9) Table 1 gives an overview of the median survival rates

for different treatment methods. Palliative treatment options are more focussed on sustaining

quality of life. Curative treatments are generally based on a multimodality treatment

(chemotherapy and radiotherapy), both in a neoadjuvant (nCRT) followed by surgery or in a

definitive setting (dCRT). Unfortunately, only 26-45% of the EC patients are eligible for

curative treatment options.(10) Moreover, even after a curative intented treatment, the local

Table 1. Median survival in months per treatment method

Treatment method Median (months) Author

Surgery only 20.3-24.0 Reeh et al., van Hagen et al.

Surgery + nCRT 49.4 van Hagen et al.

dCRT 14.4 Al-Sarraf et al.

dRT 9.0 Al-Sarraf et al.

Palliative treatment 6.0 Kole et al.

5

recurrence rate remains high ranging from 13-20.6%, whereas the overall recurrence rate of

patients treated with curative intent is around 37.9%.(11)

1.1.1 Curative treatment options

Nowadays, the primary curative treatment of locally advanced EC (T1N1-3/T2-4a N0-3)

generally consists of surgery with neoadjuvant chemoradiotherapy (nCRT). Other curative

treatment options are definitive chemoradiotherapy (dCRT) or definitive radiotherapy (dRT).

Surgery alone can be offered for localized tumors without nodal metastases (T1-2/N0),

whereas for the small less invasive (sub)mucosal lesions (T1a) endoscopic mucosal resection

(EMR) or submucosal resection (ESR) is an adequate therapy.

Different surgical procedures can be performed,

depending on the tumor type and location, tumor

stage, localization of metastatic lymph nodes and

patient characteristics: the esophagus can be

resected by a transthoracic esophagectomy (TTE;

either left- or right- sided), the transhiatal

approach (THE), or with a minimally invasive

esophagectomy (MIE). Usually the

reconstruction after resection of the esophagus is

performed by a gastric tube or colon interposition

when the stomach is not available for restoring

the upper feeding way . In both, the THE and

right-sided TTE there is a cervical anastomosis.

In our medical center, we additionally perform an

extended (D2) lymph node dissection with

removal of the upper abdominal lymph nodes

around the celiac axis (Naruke station 17-20)

(Figure 1), mediastinal (Naruke 2-7),

paraesophageal (Naruke 8), around the

pulmonary vein (Naruke 9), and the

subdiaphragmatic lymph nodes (Naruke 15 -

16).(13)

As mentioned, surgery is still the most important

factor in the curative treatment for esophageal

cancer patients. However, even after a curative intended esophagectomy, the survival

remained relatively low with a 5 years overall survival of 20-35%.(9,14) The use of additional

treatment methods, such as neoadjuvant chemoradiotherapy (nCRT) has been evaluated in the

Dutch CROSS (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study )

trial. Recently, the advanced results of this trial, using the combination of carboplatin

/paclitaxel combined with 41.4 Gy and followed by a radical transthoracic esophageal

resection sustained in improving the 5-year overall mortality rate with 10-15%, in patients

with locally advanced disease.(14) In addition, a median overall survival rate of 49.4 months

was found in the nCRT + surgery group, which is contradictory to the outcome benefits of

nCRT in some meta-analyses.(15-17) One meta- analysis included 5 randomised controlled

trials (RCTs) showing significant benefits from nCRT, while 6 other RCTs did not.(17)

However, another meta-analysis which included 22 RCTs in their analysis concluded only a

slight benefit from nCRT over surgery alone.(15) Although, there is no consensus on the

treatment benefits from nCRT in all locally advanced EC patients, the CROSS schedule is

widely used in many European centres and the generally accepted approach in The

Netherlands.

Figure 1. Naruke's lymph node mapping. Each number in the

round circles represents a lymph node station.

6

Patients who are not eligible for surgery can still be treated with curative intent, either with

definitive chemoradiotherapy (dCRT) or radiotherapy alone (dRT).(18) Several regiments of

dCRT are used throughout the world. The cisplatin/5-fluorouracil (5-FU) regiments combined

with 50.4-60 Gy radiotherapy (RT) and carboplatin/paclitaxel with 50.4-60 Gy RT are most

commonly used in the Netherlands, and have shown equal survival rates (OS).(19,20) The

median survival rate of patients receiving dCRT is 13.8-16.1 months.(20,21) Definitive

radiotherapy without chemotherapy can be used in patients who are unfit for receiving

chemotherapy. Unfortunately, the median survival rate for patients receiving only

radiotherapy is approximately 9 months.(21) Currently the role of dRT is mostly palliative

management of severe dysphagia, which gives an improvement of symptoms in the majority

(71%) of patients.(22)

EC patients with superficial tumors without infiltration into the muscular layer of the

esophageal wall (T1a/T1b) are eligible for endomucosal resection (EMR). This technique can

only be used in non-extensive tumors, less than 5cm in length and <20 mm in diameter, and

there is no suspicion on lymph node involvement.(23,24) Moreover, these tumors are usually

found in areas of Barrett’s dysplasia and frequently needed a combined treatment with

radiofrequency ablation (RFA).(25) In extent to the standard indications, the use of EMR as a

diagnostic method is currently being evaluated.

1.1.2 Palliative treatment options

Unfortunately, upon admission 20-30% of the EC patients already have metastatic disease,

and therefore cannot be treated with curative intent.(18) These patients can be treated

palliatively with radiotherapy (pRT),or chemotherapy, eventually combined with a stent or

stent only. As noted before, palliative treatment is focussed on sustaining quality of life,

specifically regarding stenosis with severe dysphagia which leads to an inadequate passage of

food and saliva, leading to unacceptable esophagotracheal aspiration especially during the

night. The median survival rate of palliative patients is low, ranging from 6-9 months.(8,21)

1.2 Staging of esophageal cancer

To ensure that EC patients receive the optimal treatment, adequate staging of the tumor is of

vital importance. Initial diagnosis and staging consists of gastroscopy with biopsies of suspect

lesions followed by computed tomography (CT), 18F-fluorodeoxyglucose positron emission

tomography (FDG-PET) or integrated PET/CT, and endoscopic ultrasonography (EUS) with

or without fine-needle aspiration (EUS or EUS-FNA).(26) As mentioned, however, the value

of the combination of each staging method and the optimal staging sequence are rather

unknown. CT and EUS are anatomic staging methods, that are based on detection of

disturbances in the anatomical structure, whereas PET and PET/CT are metabolic staging

techniques that image the uptake of radioactive glucose (18F-fluorodeoxyglucose). Another

metabolic staging method is the magnetic resonance imaging (MRI), which is currently

applied in a research setting in our institute. Combining, both anatomic and metabolic staging

techniques (PET/CT; DWI-MRI) provide the most accurate stage of the disease according to

the AJCC TNM classification (Appendix 1). Based on the current used 7th

edition of the

TNM-stage and patient condition, the individual best treatment is chosen after discussing the

pro’s and contra’s with the patient (treatment decision making process). However, the value

of EUS, as an invasive staging method in EC patients is still discutable and particularly in

patients with a poor medical condition (i.e cardiopulmonary malcondition) it seems to be low,

because these patients will more commonly be treated with surgery alone. Moreover in

symptomatic advanced stages EUS is frequently impossible or more often inadequate.

PET/CT upfront followed by selecting patients to undergo the EUS (EUS on demand) might

therefore be more useful.

7

Staging is the cornerstone for a sufficient determination of the radiation fields: by using the

combination of FDG-PET/CT and EUS appropriately, the optimal area of radiation can be

selected. Staging techniques in EC should therefore describe the location of suspicious lymph

nodes using the Naruke lymph node map (Figure 1).(13) The exact location of these node

metastases is important in treatment planning, because metastatic nodes more than 3.5 cm

outside of the primary tumor should also be adequately radiated to prevent locoregional

recurrences.(27) The area of the primary tumor together with these malignant lymph nodes is

considered as the gross tumor volume (GTV). The GTV combined with a extra margin of 3.5-

5 cm in cranial an caudal direction and 1-2 cm in transversal direction is called the CTV,

which is the actual radiation area.(28) GTV planning is normally based on information from

EUS, CT and PET/CT by the radiation oncologists.(29) The individual staging techniques are

described in the next few paragraphs.

1.2.1 Computed tomography (CT)

CT is an indispensable staging technique in EC, because of the ability to detect both lymph

node and distant metastases and their exact location as well.(30) However, the accuracy in

detecting nodal metastases is relatively low. Defining malignant versus non-malignant lymph

nodes on CT usually depends on size and shape of these nodes. Sensitivity of CT for detecting

locoregional lymph nodes is around 11-48% with a specificity of 79-99%.(30) Malignant

lymph nodes are often convex and more than 1 cm large, however lymph nodes can also be

enlarged due to reactivity on external factors such as acute or chronic inflammation

(sarcoidosis) or based on allergic response. In addition, CT lacks the ability to identify lymph

nodes as malignant within normal sized lymph nodes.(31) Therefore, the discriminatory

accuracy of malignant lymph node is only 58%.(32) Another disadvantage of CT is the

relatively long learning curve and quality of the radiologic examination on the detection of the

lymph nodes, especially in the mediastinum. Less experienced radiologists tend to miss more

possible malignant lymph nodes.(33) An advantage of CT is the detection of distant

metastases including those in the liver and lungs. CT visualizes these metastases (M1) on

routine research with a sensitivity of 40-80% and a specificity of 25-70%.(34) In addition, CT

is widely available, non-invasive and is associated with relatively low costs.

1.2.2 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT)

FDG-PET is a metabolic imaging technique that is based on entrapping phospholyrated FDG

in highly active metabolic cells, leading to a high FDG-uptake in malignant tumor cells.(35)

FDG-PET/CT scans combine the metabolic information of the PET scan with the anatomical

information from CT and are therefore able to detect tumor activity more precisely in the

whole body. FDG-PET sensitivity for detecting the primary tumor is usually high,

approximately 80-90%. However, PET scans are not suitable to define the tumor depth (T-

stage) and the exact invasion into adjacent structures. However, detection of pathological

lymph nodes gives a relatively high sensitivity of 60-100% with a specificity of respectively

83 %.(33) Earlier investigations showed that PET has an additional beneficial value of 14%

over CT in detecting node metastasis.(36) In addition, PET/CT scans are in contrast to CT

scans of thorax and abdomen, full body scans. Therefore PET/CT scans are considered as the

gold standard in detecting distant metastasis in EC, with a pooled sensitivity and specificity of

respectively, 71% and 93%.(33)

8

Unfortunately, PET is unable to detect local malignant lymph nodes directly adjacent to the

primary tumor because of a high FDG uptake in the primary tumor itself.(36) Figure 2, is an

example showing two patients who seem to have the same TNM stage, but, due to the high

FDG-uptake in the primary tumor, adjacent lymph node metastases were missed. Therefore,

the accuracy of detecting nodal metastases in EC depends on the location of the malignant

lymph nodes and ranges from 48-92 %.(36) Another disadvantage of PET/CT is the low

spatial resolution, limiting the visualisation of early carcinomas, such as T1 or even T2

stage.(36,37) Moreover, PET/CT lacks the ability to detect distant metastases smaller than

1cm in diameter, and lymph nodes with a low FDG-uptake.(38)

Figure 2. A: PET/CT of a patient staged with cT3N0M0 disease. Transversal image left, and coronal

image right. B: Hybrid PET fused with CT of a patient staged with cT3N2M0 disease. The red arrows

show the tumor location , highlighted in yellow and orange, including 3 locoregional lymph nodes.

9

1.2.3 Endoscopic ultrasonography (EUS)

EUS is the gold standard for detection of the depth of the primary tumor (T-stage) and

recognizing regional lymph nodes (N- stage). Sensitivity for defining T stage of the primary

tumor is 71% , and for recognizing regional lymph nodes with and without FNA is 93% and

63% respectively.(34) However, the reliability of EUS declines rapidly with stenosis of the

esophagus and a tumor length of > 5 cm, which is still common in locally advanced EC.(39)

EUS has an unique additional value in discriminating malignant from benign lymph nodes

because of the low rate of false negativity with the use of FNA. In addition, EUS may be

helpful in defining the treatment plan in patients with superficial EC, the T1 disease. Patients

with T1 can be treated with endoscopic resection, EMR or ESR. Meta-analysis showed that

EUS has a sensitivity of 85% to stage T1a disease and a 86% sensitivity to stage T1b disease

with specificities of 86% and 87% respectively.(40) However, a systematic review showed

that the accuracy of EUS to predict the correct T-stage of superficial esophageal cancer was

only 67%, whereas, a retrospective study on EUS in the workup of patients with early EC

showed little value of EUS in selecting patients for EMR.(41) Another study suggested that a

diagnostic EMR in patients with superficial T1 tumors without lymph node involvement

should be a better staging technique then EUS itself.(41)

Other limitations of EUS are based on its invasive character. So, the patient burden is high,

and EUS has a relative risk of aspiration, perforation and bleeding.(42) The risk of

complications increases if multiple EUS are performed and depends on a relative high

learning curve of more than 100 cases. In addition, clinical usage of EUS is further limited by

stenosis, which occurred in up to 45% of the tumors.(34) Preventing unnecessary EUS is

therefore patient-friendly and reduces the additional risks of complications.

1.3 Purpose of the study

The optimal staging sequence for EC has not been assessed yet. Currently the staging

techniques are performed in a non-specific order and the chance of unnecessary staging and

burden to the patients may be relatively high. As mentioned, recent studies have evaluated the

optimal staging and found that FDG-PET as the best predictor of curative resectability,

whereas another study found FDG-PET followed by EUS as the most cost-effective staging

sequence in EC.(7,43) The aim of this study was to investigate the additional value of EUS

after FDG-PET/CT (“PET-CT upfront”). In this PET/CT-upfront study we compared the

outcome of EUS and PET or FDG-PET/CT after the preoperative work-up, comparing the

TNM-stage before and after each separate staging technique. We were also interested in the

influence of EUS on composing a virtual treatment plan based on PET/CT only. In addition

we designed a model to select patients who should receive EUS after initial staging with

PET/CT (EUS on demand).

2. Research questions

Research question 1:

How often does EUS with or without FNA provides additional information to the

preoperative staging plan?

Research question 2:

How often does EUS influence the treatment plan based on FDG-PET/CT alone?

Research question 3:

Can we define when an EUS should be performed, based on a PET/CT upfront approach?

10

3. Patients and Methods

3.1 Patients

This retrospective study was performed according to the guidelines of approval from the local

Ethics Board and National Health Sciences rules for retrospective studies. All symptomatic

EC patients scheduled for a treatment with curative intent (T1-4a,N0-3M0), diagnosed

between 2009 and 2015 at the University Medical Center Groningen (UMCG), were eligible

for inclusion. Only patients with pathologically proven adenocarcinoma (AC) or squamous

cell carcinoma (SCC) of the esophagus or the gastro-esophageal junction (GEJ) were eligible

for inclusion. Patients with a small carcinoma (T1) that were treated with an EMR, prior to

the EUS and PET/CT, were excluded because these small lesions are often not detectable with

PET/CT. Patients who did not or were unknown in receiving a CT, FDG-PET, or FDG-

PET/CT scan were also excluded. Patients with multiple primary tumors, with missing

imaging outcomes or missing treatment data were also excluded. Table 2 (paragraph 4.1)

displays the patient characteristics.

3.2 Methods

For the purpose of this study, a database was created containing patient related-, oncologic-,

staging related-, treatment related-, and follow-up data. The patient characteristics are

displayed in table 2 and table 3 (paragraph 4.1) displays EUS related data. TNM stages of

patients who received a hybrid PET or PET scans not combined with a diagnostic CT scan,

were based on information of the PET as well as the diagnostic CT scans. If possible, hybrid

FDG-PET scans were merged with CT scans. The TNM stage of patients with combined

PET/CT scans were based solely on information of the PET/CT.

To answer the primary research question, we selected all patients with either a successful or

incomplete EUS. Patients who did not receive an EUS or with missing EUS information were

excluded from the analysis. The primary outcome of this study was whether or not EUS

provided additional information compared to PET/CT (yes/no), in which additional

information was defined as: down or upstaging of lymph nodes (N stage), detection of new

distant metastases (M stage), changes in resectability to stage T4b (irresectable yes/no), and if

EUS found additional suspicious lymph nodes or suspected nodes at other lymph node

locations according to the Naruke classification (Figure 1, paragraph 1.1.1). In addition, we

evaluated the amount of times patients received EUS + FNA, and the outcome of FNA. If

EUS+FNA was performed, EUS did gave additional information no matter what the outcome

of EUS was. The outcome was displayed as a percentage of patients in which EUS provided

additional information compared to PET/CT. Table 4 (paragraph 4.2) displays the additional

value of EUS according to our definition.

The secondary outcome was how often EUS influenced the treatment planning if it was

performed after PET/CT alone (yes or no). In order to answer the second research question,

we selected all patients with either a successful or incomplete EUS. Patients who did not

receive an EUS were excluded from analysis. As mentioned earlier, treatment decisions

(decision for surgery, nCRT, dCRT or dRT with curative intent or palliative care) were based

on the outcome of all imaging techniques. We retrospectively evaluated the influence of EUS

on the treatment decision that was made at the time and assessed how often EUS changed the

treatment decision. Influence of EUS on the treatment was scored as EUS changed the

treatment yes or no. The influence of EUS on the treatment was first defined for the entire

group and then for each individual group (decision for surgery, nCRT, dCRT or dRT). First,

we assessed how often EUS resulted in a change of treatment intent, either from curative to

palliative or the other way round (because of a change in resectability or detection of distant

metastases). Then we assessed the influence of EUS in the different treatment groups (nCRT,

dCRT, surgery, dRT and the palliative group).

11

In the nCRT, dCRT, and the dRT group, EUS changed the treatment if lymph node

metastases were found in non-regional or lymph node stations (Figure 1, paragraph 1.1.1),

that were not located adjacent to the primary tumor (<3.5 cm, based on Muijs et al.) or

adjacent to lymph node metastases found with PET/CT. Figure 4 (paragraph 4.3) displays the

amount of times EUS influenced treatment within the different treatment groups. In the

surgery group, EUS only changed the treatment if lymph nodes were located outside of the

D2 lymph node resection area (outside of Naruke station 3-7, 8, 15-20). These patients were

however, most often treated with dCRT because the lymph node metastases were located

outside of the D2 resection area. In the palliative group we defined treatment change

according to the change of the palliative radiation area. The outcome was displayed as the

percentage of patients in which EUS changed the treatment.

The third research question was if whether or not we could retrospectively define when an

EUS should be performed based on information of the PET/CT. We therefore evaluated if

EUS was necessary (yes/no) according to our conditions and if these selected patients actually

had a useful EUS . We therefore defined when an EUS was necessary based on the PET/CT,

namely: if PET/CT found lymph nodes outside the GTV according to Muijs et al., if there was

doubt about the resectability (T4b), if a patient could receive an EMR, and if possible distant

(lymph node) metastasis were found that could be confirmed with EUS.(23) The outcome was

the usefulness of the EUS, in which a useful EUS was defined as: an EUS that found positive

lymph nodes outside the PET/CT defined GTV, an EUS that confirmed the PET/CT defined

GTV, and an EUS that found T4b or M1 disease in cases where PET/CT did not.

To test our definition of an useful EUS that was necessary based on the PET/CT, we selected

all patients with a successful or incomplete EUS. Patients without an EUS were excluded

because it is unknown whether or not EUS would provide additional information. In addition,

we also excluded patients who were treated with surgery alone because these patients should

not benefit from an EUS, even if it would have provided additional information regarding the

probably given nCRT. Table 5 (paragraph 4.4) displays the amount of times EUS was

necessary or not according to our definition, in relationship to the amount of times EUS was

useful. We then used a Chi-square analysis comparing our definition with the useful EUS.

3.3 Staging Patients were staged according to the 6th or 7th TNM classification of the American Joint

Committee on Cancer (AJCC) with gastroscopy, hybrid FDG-PET, FDG-PET/CT, CT and

EUS.(6,44) Patients staged according to the 6th edition were restaged to the 7th TNM edition.

All staging methods were evaluated and discussed in a multidisciplinary meeting with

members of the departments of Oncology, Radiology, Radiotherapy, Gastroenterology,

Oncologic Surgery, Nuclear Medicine and Pathology, resulting in a clinical TNM stage. All

abnormalities and possible distant metastasis found during initial staging (with FDG-PET/CT,

CT or EUS) were either proven pathologically or assessed with additional imaging

techniques: such as magnetic resonance imaging (MRI), additional EUS with FNA, or

external ultrasound including biopsy.

3.3.1 Endoscopic ultrasonography (EUS)

In our tertiary medical center, the EUS were performed by EUS specialized

gastroenterologists . With EUS, the depth of invasion of the tumor (T-stage), amount of

lymph node metastasis (N-stage), tumor location, and tumor length was assessed and noted.

All EUS were performed under sedation, using midazolam intravenously. The EUS were

performed using a radial or linear endoechoscope scanner (GF-UM20, Olympus Medical

Systems, Tokyo, Japan or EG3870UTK, Pentax, Benelux, Breda, The Netherlands) and EUS-

12

guided FNA of suspect lymph nodes was performed using a linear endoechoscope

(EG3870UTK, Pentax, Benelux, Breda, The Netherlands). In case of stenosis a small-caliber

probe (paediatric scope) was used (MH-908, 7.5 MHz; Olympus Medical Systems, Tokyo,

Japan). If passage of the scope was unsuccessful or incomplete, the length until stenosis and

malignant lymph nodes proximal of the tumor were reported. Reasons for incomplete EUS

were reported, as well as reasons for not performing a EUS.

3.3.2 Computed tomography (CT)

Thorax, abdominal and total body CT scans were performed, depending on the local hospital

where the CT scan was made. In case of inadequate CT at the rural hospital a 64 mCT staging

was always reperformed in our center. All patients underwent a 16-64 multislice CT scan

with intravenous or oral contrast fluid, and images were 1.5 to 5 mm slices respectively.

Mediastinal and para-esophageal lymph nodes were assessed as lymph node suspect for

metastasis if the diameter exceeded 1 cm.(45,46) Supra-clavicular lymph nodes exceeding 5

mm in diameter and retrocrural lymph nodes exceeding 6 mm in diameter were marked as

malignant.(47)

In some cases, additional diagnostic non-contrast CT scans have been made, because the

original CT scans had a poor quality or were incomplete. Information found on these CT

scans was only considered if patient had received a hybrid FDG-PET without combined CT

scans.

3.3.3 18F-fluorodeoxyglucose - positron emission tomography (FDG-PET)

FDG-PET and FDG-PET/CT scans were performed at different medical centres using either a

Siemens or Philips system (Siemens, Germany; Philips Gemini, DA Best, The Netherlands).

All patients received a FDG-PET or PET/CT scan after at least 4 hours of fasting. Upon

admission 555-740 MBq (15-20 mCi; 0.22 mCi/kg) was given intravenously, and after 60 min

images were obtained. Integrated FDG-PET/CT scan used a non-contrast CT scan for

comparison. Images were made from skull to the mid-thigh region, divided in 2,5-5 mm

slices, depending on the medical centre. 18F-FDG uptake was compared with the non-contrast

CT scan or external CT scan. Nuclear physicians assessed the FDG uptake per image after a

three dimensional representation was made. 18F-FDG uptake outside physiological areas

were defined as malignancies.

3.4 Treatment

Neoadjuvant chemoradiotherapy (nCRT) consisted of a 5 week schedule of radiotherapy with

a total dose of 41.4 Gy given in 23 fractions of 1.8Gy combined with five administrations of

a combination of carboplatin (area under the curve = 2 ml/min) and paclitaxel (50 mg/m2)

during RT at day 1, 8, 15, 22, 29 according to the CROSS regimen.(14) Definitive chemo

radiotherapy was given depending on patient characteristics, consisting of 40-60Gy in 30

fractions/week in combination with 50 mg/m2 carboplatin/paclitaxel or a combination of

cisplatinum 75 mg/m2 (day 1) of each week and 5-FU 1g/m2 (day 1-4) at week 1 and 5, 8 and

11 during radiotherapy (RT), with two additional courses on week 8 and 11, according to the

RTOG 85-01 scheme.(48)

In our tertiary medical center, surgery was performed by two teams of experienced surgeons.

The standard surgical procedures in our medical center were a transthoracic procedure, which

was either performed through a left thoracolaparotomy with an intrathoracic anastomosis

(Sweet procedure) or a right thoracolaparotomy with a cervical or intrathoracic anastomosis

(Ivor-Lewis or McKneown procedure).

13

3.5 Statistical analysis

Descriptive analysis was performed. All categorical data were displayed as numbers or

proportions (percentages). Parametric continues data were displayed as means with standard

deviation (SD), non-parametric data were displayed as median interquartile ranges (IQR). All

data were analyzed using SPSS statistical software, version 22 (SPSS inc., Chigago, IL,

USA).

A multivariate binary logistic regression was used to assess which factors were likely to

result in stenosis. We used a chi-square test to evaluate the amount of times EUS gave

additional information between the successful and incomplete group, and to answer the third

research question regarding the usefulness of EUS after PET-CT upfront comparing an useful

EUS with the amount of times EUS was necessary according to our definition as defined in

paragraph 3.2. P value < 0.05 was defined as significant.

14

Patients diagnosed with esophageal cancer

Stage T1-4a,N0-3M0

N= 343 patients

Missing data

N = 2

Histology other than AC or

SCC

N = 8

Patients included

N= 299

Missing PET or PET/CT

N = 18

Multiple primary tumors

N = 2

EMR prior to PET/CT

N = 11

No visible malignancy on PET/

CT

N=3

Table 2 abbreviations : y= years, IQR= interquartile range,

cm=centimeters, std. = standard deviation, Mid = mid-

esophageal, GEJ = gastro esophageal junction , cT/N = clinical

T/N stage, pT/N = pathological T/N stage, nCRT= neoadjuvant

chemo radiotherapy, dCRT = definitive chemo radiotherapy,

dRT = definite radiotherapy

4. Results

4.1 Study population

In total, three hundred and forty-three

(n=343) esophageal cancer patients,

treated at the University Medical

Center Groningen (UMCG), were

eligible for inclusion (Figure 3). A total

of forty-four (n=44) patients were

excluded: Eighteen (n=18) patients

were excluded because of a missing

PET or PET/CT scans, two patients

(n=2) had missing data (both regarding

decision of treatment), eight patients

(n=8) had different histopathologic

tumor types than AC or SCC, two

patients (n=2) had two primary tumors,

eleven patients (n=11) received an

EMR prior to the PET/CT scan, and

three patients (n=3) had no visible

malignancy on PET/CT. A total of two

hundred and ninety-nine patients

(n=299) were included in the analysis.

Table 2. Patient characteristics and demographic data

Number of patients (n=299)

Male 223 (74.6%)

Age (y), median (IQR) 65 (60-70)

Tumor length (cm), mean (std) 5.3 (2.6)

Histology

Adenocarcinoma 216 (72.2%)

Squamous cell carcinoma 83 (27.8%)

Tumor location

Proximal 12 (4.0%)

Mid 53 (17.7%)

Distal 184 (61.5%)

GEJ 50 (16.7%)

Clinical T stage

cTx 6 (2.0%)

cT1 16 (5.4%)

cT2 38 (12.7%)

cT3 209 (69.9%)

cT4a 30 (10.0%)

Clinical N stage

cN0 74 (24.7%)

cN1 120 (40.1%)

cN2 91 (30.4%)

cN3 12 (4.0%)

cNx 2 (0.7%)

Treatment

Surgery 57 (19.1%)

nCRT 157 (52.5%)

dCRT 62 (20.7%)

dRT 14 (4.7%)

Palliative 9 (3.0%)

Death < 90 days 21 (7.0%)

Recurrence < 3 months

No 251 (83.9%)

Yes 14 (4.7%)

Unknown 13 (4.3%)

Figure 3. Flowchart illustrating the exclusion

process.

15

Table 2 displays the patient characteristics and demographic data. The median age was 65

(IQR 60-70) years and two hundred and twenty-three patients (n=223, 74.6%) were men. Two

hundred and sixteen patients (n=216, 72.2%) had an adenocarcinoma (AC), whereas only 83

patients (n=83, 27.8% ) had squamous cell carcinoma (SCC). Most tumors, 61.5% (n=184)

were located in the distal esophagus, followed by the mid-esophageal region, 17.7% (n=53),

and the gastro-esophageal junction (GEJ) 16,7% (n=50). Of the total group, one hundred and

fifty seven patients (n=157, 52.7%) were treated with nCRT, sixty two (n=62, 20.7%) were

treated with dCRT, fifty-seven (n=57, 19.1%) were treated with surgery alone, and fourteen

(n=14, 4.7%) with definitive radiotherapy. Of the fifty-seven patients treated with surgery

alone, twenty-six (n=26, 46.4%) patients had severe co-morbidities and were therefore not

eligible for nCRT. Sixteen (n=16, 28.6%) patients had a primary resectable tumor, and

fourteen (n=14, 25.0%) were treated before nCRT became the standard of care. Although, all

included patients could have been treated with a curative intent based on the primary tumor

characteristics, nine patients (n=9, 3.0%) were treated with palliative intent because of severe

co-morbidities, high age or patients preferences.

A total of one hundred and eighty-seven patients (n= 187, 62.5%) had a successful EUS

(Table 3), fifty seven (n= 57, 19.1%) had an incomplete EUS, and EUS was not performed in

fifty-five (n=55, 18.4%) patients. Stenosis was the only reported cause for an incomplete EUS

in all fifty seven patients (n=57, 100%). Reasons for not performing an EUS included:

stenosis (n=47, 83.9%), esophageal bleeding (n=2, 3.6%), severe vomiting during

examination (n=2, 3.6%) , unknown reason (n=2, 3.6%), and because the EUS would not

added any benefit to the patient (n=2, 3.6%).

Further evaluation of the data displayed that one hundred sixteen patients (n=116,45.6%) first

had a PET/CT (PET/CT upfront) and one hundred thirty eight patients (n=138,54.4%) first

had a EUS (EUS upfront). There were five patients (n=5) who underwent a second EUS, of

which three patients (n=3) had a PET/CT upfront and two patients (n=2) had the EUS upfront.

Because stenosis was the only reported cause of no EUS we assessed if stenosis was

significantly more often found with a tumorlength < 5 cm or > 5 cm, in AC or SCC or if

located in the upper or lower esophagus. The upper esophagus was defined as proximal or

medial location, distal esophagus was defined as distal or GEJ location. A multivariate

logistic regression analysis found that a tumor length >5cm and patients with SCC

significantly more often had a stenosis (P =0.29 an P=0.4 respectively).

4.2 The additional value of EUS after PET/CT After selection of patients with either a successful or incomplete EUS, two hundred and forty-

four patients (n=244) were included in the analysis. According to our definition EUS gave

additional information in one hundred and sixty-nine patients (n=169, 69.3%), displayed in

table 4. Ninety-five patients (n=95, 56.2%) had an upstaging of N-stage after EUS, twenty-

Table 3. Descriptive data of EUS

Number of patients (n =299)

EUS complete 187 62.5%

EUS incomplete 57 19.1%

Stenosis 57 100%

EUS not performed 55 18.4%

Stenosis 47 85.5%

Patient dependent 4 7.3%

On indication no EUS 2 3.6%

Unknown 2 3.6%

16

seven (n=27, 16.0%) had a lower N-stage after EUS, forty-seven (n=47, 27.8%) had changes

in lymph node location after EUS, three (n=3, 1.8%) had a changed resectability after EUS,

and no patients (0.0%) had distant metastasis found with the EUS (n=0, 0%). The changes in

resectability were two patients (n=2, 66.7%) that had a possible T4b disease on PET/CT and

one patient (n=1, 33.3%) had a possible adrenal metastasis on PET/CT which was negative on

EUS.

In addition, we assessed the amount of times fine needle aspiration (FNA) was performed in

the patients with successful or incomplete EUS; thirty-five patients (n=35, 14,2%) had FNA

of a suspect lymph node, of which twenty-one FNA (n=21, 60%) were positive for metastasis

and fourteen (n=14, 40%) were negative. All these patients were additionally considered as

patients in which EUS provided additional information, however all these patients had already

been scored as patients in which EUS gave additional information.

4.3 Influence of EUS on treatment after PET/CT

To answer our second research question we selected patients with either a successful or

incomplete EUS. Two hundred and forty-four patients (n=244) were included in the analysis.

We retrospectively assessed the influence of EUS within the treatment groups. Of all included

patients EUS changed the intention of the treatment in just one case (n=1, 0.4%) from

possible palliative to curative. This patient had a possible adrenal metastasis on PET/CT and

EUS showed an adenoma of the adrenal gland. Then we assessed the influence of EUS on the

treatment: In the total group (n=244) EUS changed treatment in sixty-nine patients (n=69,

28%). The amount of treatment changes because of EUS was significantly higher in the group

with a successful EUS (n=59, 85.5%) as compared to the incomplete EUS (n=10, 14.5%)

(P=0.04).

All patients with AC/SCC esophageal cancer staged with

PET/CT and had stage T1-4aN0-3

Palliative

(n=5)

dRT

(n=11)

dCRT

(n=35)

nCRT

(n=142)

Surgery

(n=51)

No

(n=3)

No

(n=7)

No

(n=27)

No

(n=87)

No

(n=51)

Yes

(n=2)

Yes

(n=4)

Yes

(n=8)

Yes

(n=55)

Yes

(n=0)

Patients with incomplete or successful EUS

244 patients

Table 4. The additional value of EUS after PET/CT among patients with successful or incomplete EUS

Number of patients (n=244)

EUS gave no additional information 75 30.7%

EUS gave additional information 169 69.3%

Upstaging of N-stage 95 56.2%

Downstaging of N-stage 27 16.0%

No change of N-stage 47 27.8%

Change of resectability 3 1.8%

New distant metastasis 0 0%

Figure 4. Flowdiagram showing the changes in treatment because of EUS on treatment in the separate treatment

groups

17

Thereafter we assessed the influence of EUS on the treatment in the different treatment

groups (Figure 4). EUS did not change the treatment in the surgery group (n=51) because

there was no additional information with respect of suspicious lymph nodes outside the

locoregional area or D2 resection area (Figure 4). In the nCRT group (n=142) EUS changed

the treatment in fifty-five patients (n=55, 38.7%). In the dCRT group (n=35) EUS changed

the treatment in eight patients (n=8, 22.9%). In the dRT group (n=11) EUS changed the

treatment in four patients (n=4, 36.4%). In the palliative group (n=5), EUS would have

changed the treatment in two patients (n=2, 40%) if the patients would have been healthy

enough to receive radiation therapy. However, these two patients received a stent instead of

palliative radiotherapy because of the patients preferences.

4.4 Designing a definition to predict whether an EUS is necessary

To answer the third research question we defined when a useful EUS should be made, based

on the PET/CT. Therefore we included all patients with a successful or incomplete EUS. In

addition, we excluded forty patients (n=40) who were treated with surgery alone because of

co-morbidities, as described in paragraph 3.2. A total of two hundred and eight patients

(n=208) were eligible for analysis. We found EUS to be useful according to our definition in

one hundred and four patients (n=104, 50%). EUS found positive lymph nodes outside the

PET/CT GTV, and therefore changed the CTV, in 25.5% of the cases (n=53), confirmed

PET/CT GTV in 11.1% (n=23), changed GTV based on EUS after PET/CT in 12.0% (n=25),

and finally found T4b in 1.4% of the patients (n=3).

According to our definition, EUS was necessary based on PET/CT in one hundred and

twenty-one patients (n=121, 58.2%), in seventy-three (n=73, 35.1%) of these patients EUS

was useful (Table 5). EUS was not necessary according to our definitions in eighty-seven

patients (n=87, 41.8%). However, in thirty-one of these patients (n=31, 14.9%) EUS was

found to be useful.

With chi-square analysis, we found that the patients who should receive an EUS according to

our definition (“EUS on demand”) had significantly (P<0.001) a more useful EUS, than the

group that should not receive an EUS according to our definition.

Table 5. EUS useful in comparison with EUS necessary

EUS useful EUS not useful

Based on PET/CT EUS was necessary 73 (35.1%) 48 (23.1%)

EUS was not necessary 31 (14.9%) 56 (26.9%)

18

5. Discussion

Tumor staging is of vital importance in EC to determine the optimal treatment. In our medical

centre, patients are staged with a combination of CT, PET/CT, and EUS. However, there is no

consensus about the optimal staging sequence in EC patients. Therefore we assessed the

additional value and influence of EUS on treatment decision making after FDG-PET/CT up

front. In this study, EUS gave additional information in 66.7% of the patients, but only

changed the treatment planning in 28%. We also assessed if we could select patients with

PET/CT (PET/CT upfront), who would benefit from an EUS. And found that patients who

should receive an EUS according to our definition (EUS on demand), significantly more often

received a useful EUS. However, according to the protocol with our pre-definition we had

missed 31 patients (14.9%) who would have benefited from EUS.

EUS is the best staging technique to assess the depth of tumor invasion (T-stage) and lymph

node involvement (N-stage) with a sensitivity of 71% and 63%, respectively. Whereas,

PET/CT on the other hand has a sensitivity of only 60% in determining the T-stage and

between 60-100% in determining the N-stage.(33,34) However, not all patients will benefit

from EUS. Especially patients with stenosis do not benefit from EUS, because passage of the

endoscope is impossible or incomplete, leading to an inadequate staging procedure with EUS

and therefore no treatment benefit could be achieved. In this study, 34.7% (104 of 299

patients) had a stenosis: 19.1% (57 of 299 patients) had an incomplete EUS due to stenosis,

and in 15.7% (47 of 299 patients) EUS was not performed because of severe stenosis. The

findings in our study were in line with the 35-45% of patients with stenosis found in recent

literature.(34) The value of an incomplete EUS on treatment planning is very low, due to a

relative high chance of understaging or insufficient staging. In this study EUS provided

additional information in 23 patients (14.5%) and influenced treatment in ten patients (n=10,

17.5%) with an incomplete EUS.

Recent studies have suggested to dilate the stenosis to be able to perform a successful EUS. A

very small study by Worell et al. suggested that dilatation of the stenotic esophageal wall

should be omitted because of the advantages of adequate staging. (49) In addition, Pfau et al.

concluded that dilation up to 14 mm in diameter was a safe and possible manner to allow

complete EUS staging.(50) However, dilatation of malignant structures has a risk on

perforation, 6.9%, resulting in a high mortality and also higher chance of recurrent disease

due to seeding of malignant cells into different cavities (mediastinum/pleural space).(51)

Because of these risks, dilation of the stenotic tumor is not a standard and not often

performed in the Netherlands. In addition, we found that stenosis occurred significantly more

often in patients with a tumor length of more than 5 cm and if the patient had SCC. As

mentioned, EUS is less reliable in patients with a tumor length of more than 5 cm.(39)

This study is one of the first to assess the additional value and influence on the given

treatment of EUS after PET/CT (PET/CT upfront). We found that the additional value of EUS

after PET/CT upfront did not necessarily changed the treatment of EC patients: EUS changed

the treatment in only 28% of the cases (n=244). The main additional value of the EUS was a

more adequate lymph node staging (N-stage), leading to both an up (56.2%) and down staging

(19%) effect, which however does not necessarily influence the treatment decision making.

The N-stage in the clinical (c)TNM classification, although important in the clinical decision

making, does not provide adequate information about the location of LN metastasis. The cN-

stage, which is based only on the presentation of total number (N0 - N3) of clinical suspicious

lymph nodes, is far from optimal (Appendix 1). Moreover, most patients already have locally

advanced disease, usually with nodal involvement (T2-4aN0, T1-4aN1-3), at the time of

presentation. The primary curative treatment for locally advanced EC is nCRT followed by

surgery. During this treatment, the chemotherapy sensitises the tumor cells for the

19

radiotherapy and thereby increases the tumor response.(14) In order to achieve full tumor

response in the lymph nodes, malignant LNs should be located within the radiation field

(paragraph 1.2), especially within the gross tumor volume (GTV). Suspected LNs, which have

been detected during staging, but located outside the primary radiation area, should therefore

be irradiated additionally. We therefore assessed the value of EUS in detecting suspicious

LNs >3.5 cm from the cranial and caudal GTV and 1 cm from the transversal GTV. In our

study EUS found lymph nodes located outside the primary GTV in 36.1 % after PET/CT. We

also examined the value of EUS in the recent literature. A meta-analysis performed by

Westereenen et al. found that EUS has an incremental value on excluding potential positive

LNs, being more accurate than CT or FDG-PET/CT, meaning that positive LNs found on

PET/CT can be staged more precisely with EUS.(33) The pooled sensitivity of PET(/CT) to

find locoregional LNs was 57%.(33) The PET/CT upfront cannot detect LNs located directly

adjacent to the primary tumor. However, because most of these adjacent LNs are found within

the GTV, these lymph nodes do not have a great influence on the radiation fields.

In addition to the role of the N-stage in the clinical decision making, the T stage is also not

always important for clinical decision making: the T-stage is only important for clinical

decision making in patients with stage T1 and T4b. The staging of T1a-T1b tumor is difficult

with PET/CT upfront: PET/CT has a low spatial resolution, resulting in a low accuracy to

detect small superficial tumors.(52) EUS on the other hand has a high sensitivity of 85% and

86% for T1aN0 and T1bN0 disease, respectively.(40) The usefulness of EUS can however be

debated, other techniques can also be used: Recently, Pouw et al. suggested that a diagnostic

EMR is the best staging option in early esophageal cancer found during endoscopy.(41) In our

medical center, we perform a diagnostic EMR on selected patients with superficial lesions and

based on the pathologic outcome, patients receive the standardized follow-up (EUS and

PET/CT) or are treated with surgery alone. However, Ide et al. showed that lymph node

involvement (N+) is directly related to the T-stage with a chance on LN involvement of

24.5% in patients with T1a squamous cell carcinoma, in addition Buskens et al. found that

patients with T1a adenocarcinoma only had LN metastases in 2% of the cases.(53,54)

Diagnostic EMRs to assess the superficial tumor growth might therefore be an option.

In detecting patients with T4b disease and to discriminate between the still resectable T4a and

irresectable T4b, the role of EUS is more important: EUS detects T4b disease with an

accuracy of 84%.(55) However, depending on the location of the tumor or involvement of the

surrounding area (aorta, trachea), other techniques can also be necessary. CT has a high

sensitivity to find ingrowth of the tumor into aorta or trachea. In addition, endoscopic

broncho-ultrasonography (EBUS) is a very effective method to evaluate the ingrowth of the

tumor into the bronchus. In our study, we had zero patients (n=0) with T4b disease found with

EUS after PET/CT. Therefore we could not assess the specific role of EUS in patients with

T4b disease. Of note, all patients with T4b on PET or CT had been excluded from analysis.

PET/CT upfront as a first staging approach followed by an indicated EUS (EUS on demand)

would potentially be the best staging sequence. One of the studies previously done by

Schreurs et al. assessed the optimal staging sequence to determine the resectability and found

that the model with the PET upfront followed by an EUS was the best predictor of curative

resectability.(7) However, Schreurs et al. did not assess the clinical value and the effect on the

treatment. Another study by Westereenen et al. assessed the amount of unnecessary surgeries

between different preoperative staging sequences and found that FDG-PET was the

significant predictor of curative resectability. Westereenen et al. also found that FDG-PET is

reducing unnecessary surgery with 23%.(56) These studies however, only included the

influence of the staging sequence on the resectability and did not assess the influence of EUS

on the given treatments i.e nCRT. We found that FDG-PET/CT upfront would have prevented

20

unnecessary EUS, if performed on our conditions, in 26.9% of the cases. PET/CT upfront is

not only the preferred method because of the tumor-staging, but also cost-effective. In a cost-

analysis Wallace et al. found that the combination of PET/CT followed with EUS-FNA was

the most cost-effective.(43)

This study has several limitations. First, the retrospective nature of this study: Not all lymph

node locations were accurately described and the rationale for a treatment was sometimes

unclear. In some patients, it was difficult to assess the distances between the primary tumor

and malignant lymph nodes, retrospectively. However, most of the suspicious lymph nodes

that influenced the determination of the radiation area were located in LN stations that were

>3.5 cm from the primary tumor and therefore outside the primary GTV. In our study we used

the clinical tumor volume (CTV), defined as an area of 2 cm from the GTV, as a measure for

treatment change according to the study of Muijs et al..(27) If there were lymph nodes outside

the CTV area, we assumed treatment would have changed. In patients treated without

radiotherapy, but with surgery alone, would not benefit by a change in CTV and the additional

EUS information would not be useful in any case. In determining the influence of lymph node

location on the radiation area, most of the patients in which EUS had an additional value were

in the group treated with nCRT (79.7%). Besides, there were no surgical only treated patients

who benefitted from the EUS. As these patients underwent a regular mediastinal and upper

abdominal nodal dissection, the surgical specimen of these patients with a pathological radical

resection included all the previous mentioned suspicious nodes. Although unclear, the value

of EUS is probably the same in patients who are medically unfit due to comorbidities for the

trimodality treatment and nevertheless were treated surgically. Therefore, EUS may probably

also be withheld from these patients in the future.

What should always be kept in mind is that all staging modalities have an inter-observer

variability, but specifically the EUS requires highly trained and specialised endoscopists.

Furthermore, different staging techniques have been used (PET + CT vs. hybrid or integrated

PET/CT) over the past few years. This is a continued process and nowadays the additional

staging with diffuse weighted magnetic resonance imaging (DWI-MRI) seems to give more

specific information with respect to the N-stage. Most patients staged before 2010 received a

PET combined with a CT, while the majority of patients staged after 2010 received an

integrated PET/CT scan. The integrated PET/CT resulted in a better spatial resolution, which

is one of the major disadvantages of PET alone. The integrated PET/CT upfront scans might

have an increased accuracy compared to the separately fused PET and CT. Bar-Shalom et al.

found that the overall accuracy of PET is 83% and the accuracy of PET/CT is 90%.(57)

In addition, our selection criteria might also influence the outcome of this study. We only

included patients with potentially curable disease (T1-4aN0-3M0) and excluded patients with

distant metastasis or involvement of the adjacent structures on the PET/CT or CT. The reason

we excluded these patients was because PET/CT has already been proven to be the best

selection method in assessing treatment with curative intent. The patient group we included is

a selected group of EC patients who might also have the most benefit from EUS. To answer

the different research questions, we therefore used different selection criteria: because the

inclusion of patients without an EUS would bias the results of the first and second research

question. To answer the third research question, we excluded patients that were treated with

surgery alone because of co morbidities, because these would not have benefitted from EUS

in any circumstance.

In conclusion, we found that although EUS provided additional staging information after

PET/CT in 69.3%, it only changed the given treatment in 28%. EUS is therefore, not always

an obliged approach. Selecting patients who might not benefit from EUS, will decrease the

21

use of unnecessary EUS and might be cost-effective as well. Especially, patients with known

stenosis during diagnostic gastroscopy might be saved from a unnecessary EUS, with a

PET/CT upfront. We therefore assessed whether we could select those EC patients that would

benefit from EUS, based on PET/CT upfront. Though “EUS on demand” lead to a

significantly more useful EUS in the group already selected with “PET/CT upfront”, 14.9% of

the total patient group would not have received a EUS that might influence the treatment

decision. Therefore, based on this retrospective study, EUS can partly be used on indication

after PET/CT. However, in order to adequately select patients who might benefit from a EUS,

additional research should be performed to optimalize the definitions of the “EUS on

demand”. We propose a large prospective study on the value of EUS on indication of PET/CT

should be designed, to evaluate the optimal staging sequence in patients with esophageal

cancer.

6. Acknowledgements I would like to thank Jan Binne Hulshoff, Bsc; Justin Smit, MD PhD and prof. dr. J.T.M.

Plukker MD.PhD, for their support to perform this master thesis. Special thanks to Marijn de

Jong, LLM and my parents, for their support.

7. List of Abbreviations

(in alphabetical order)

AC = Adenocarcinoma

AJCC = American Joint Committee on Cancer

CT = Computed tomography

CTV = Clinical tumor volume

dCRT = Definitive chemoradiotherapy

DWI-MRI = Diffuse weighted magnetic resonance imaging

EBUS = Endobronchial ultrasonography

EC = Esophageal cancer

EMR = Endoscopic mucosal resection

ESR = Endoscopic submucosal resection

EUS = Endoscopic ultrasonography

FDG = 18F-Fluorodeoxyglucose

FNA = Fine needle aspiration

GTV = Gross tumor volume

LN = Lymph node

nCRT = Neoadjuvant chemoradiotherapy

OS = Overall survival

PET = Positron emission tomography

RFA = Radiofrequence ablation

RT = Radiotherapy

SCC = Squamous cell carcinoma

22

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Appendix 1

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