UNIVERSITY OF MEDICINE AND PHARMACY „GR. T. POPA” IAȘI

PhD Thesis

Summary

ROLE OF SURGICAL TREATMENT IN EARLY AND

ONCOLOGICAL PROGNOSIS FOR PATIENTS WITH

ESOPHAGEAL CANCER

SCIENTIFIC COORDINATOR,

PROFESSOR DR. SCRIPCARIU Viorel

PhD STUDENT,

FILIP Bogdan

2014

Invest in people!

Research funded form the European Social Fund through the Operational

Program for Human Resources Development 2007-2013.

Prioritary Axis 1 „Education and professional development for economic

growth and social development based on knowledge”

Main intervention field 1.5 „Doctoral and post-doctoral program supporting

the research”

Project title: „Interuniversitary partnership to increase the quality and

interdisciplinarity of the research through doctoral fellowships –

DocMed.net”

Contract Code: POSDRU/107/1.5/S/78702

Beneficiary : University of Medicine and Pharmacy „Iuliu Hațieganu” CLUJ-

NAPOCA

Partner 1: University of Medicine and Pharmacy „Gr. T. Popa” IAȘI

Key words: esophageal cancer, esophagectomy, prognostic scores, minimally

invasive esophagectomy, survival

The thesis consists of:

- Theory (39 pages) in Five Chapters

- Personal research (95 pages) in five Chapters

- 408 references

- 49 pictures

- 55 tables

- 4 B+ articles and 2 ISI indexed published or accepted articles

In this abstract, the table of contents and the number for each figure is the same as

in the thesis.

Table of contents

Personal motivations

General part

Chapter 1. General notions regarding esophageal cancer

1.1. Epidemiology

1.2. Etiology

1.2.1. Risk factors for the development of squamocellular tumours

1.2.2. Risk factors for the development of adenocarcinomas

1.3. Pathology

Chapter 2. Diagnosis of esophageal cancer

2.1. Initial diagnosis tests

2.2. Preoperative staging

2.3. Prognostic scores in esophageal surgery

Chapter 3. Surgical treatment of esophageal cancer

3.1. Classical surgical treatment

3.1.1. Clasic esophagectomy techniques

3.1.2. Minimally invasive esophagectomy

3.2. Surgical treatment based on tumour localisation

3.3. Early postoperative outcomes. Morbidity and mortality

3.4. Late postoperative outcomes – recurrence and survival

3.5. Quality of life in patients operated for esophageal cancer

Chapter 4. Sentinel lymph node concept in esophageal cancer surery- a meta-

analysis of studies

4.1. Study characteristics

4.2. Diagnostic procedures for sentinel lymph node detection

4.3. Individual studies results

Chapter 5. Radio and chemotherapy treatment

5.1. Managment of locally advanced stages

5.1.1. Neoadjuvant treatment

5.1.2. Adjuvant treatment

5.2. Palliative treatment of unresectable tumours

5.3. Therapeutic indications

PERSONAL CONTRIBUTIONS

CHAPTER 6. Evaluation of risk factors involved in the occurence of postoperative

complications after esophagectomy

6.1. Aim of the study

6.2. Material and methods

6.2.1. statistical analysis

6.3. Results

6.4. Discussions

CHAPTER 7. Minimally invasive esophagectomy for esophageal cancer

7.1. Aim of the study

7.2. Material and methods

7.3. Results

7.4. Discussions

CHAPTER 8. Survival analysis in patients operated for esophageal cancer based

on the response of neoadjuvant treatment

8.1. Aim of the study

8.2. Materials and methods

8.2.1. Statistical analysis

8.3. Results

8.4. Discussions

CHAPTER 9. Comparative study regarding early postoperative outcomes based on

surgical approach for esophagectomy

9.1. Aim of the study

9.2. Material and methods

9.3. Results

9.4. Discussions

CHAPTER 10. Final discussions and conclusions

10.1. Discussions

10.2. Final conclusions

References

Addende

Abbreviations

List of scientific papers issued during PhD studies

Personal Motivations

There is an actual increase of esophageal cancer incidence in

Western Europe with relatively stable incidence for the Eastern Europe.

The results of life style changes, nutritional factors and the new methods

for screening are the increased incidence of adenocarcinomas of the lower

esophagus or of the gastro-esophageal junction. This epidemiological shift

occurred in a two decade interval, until then, most of the tumours were

represented by the scuamocellular cancers in heavy smokers and alcohol

consumers. In Romania, esophageal cancer has an estimated incidence for

2012 of 5.9/100.000 inhabitants with approximatively 655 newly diagnosed

cases (1). Unfortunately, most of the cases are still represented by

scuamocellular tumours, developed in patients with above mentioned risk

factors. Actual incidence of adenocarcinomas is low, but it is estimated that

two decades from now, its incidence will grow, probably due to the life

style changes and nutritional factors for the population at risk. This

represents the period for the onset of the chronic lesions of Barrett

esophagitis and the development of esophageal adenocarcinoma (2). Most

of the esophageal tumours are diagnosed in advanced stages. Classical

clinical presentation such as disphagia or pain on swallowing occure in

patients with gross tumours obstructing the passage. More frequent

esophageal cancer presents an early lymphatic and hematogenic spread.

Based on those considerations, over 50% of newly diagnosed patients are

considered to be unresectable due to the local invasion or the metastatic

disease (3). Esophagectomy is associated with a high surgical and

anaesthetic risk. Although in present postoperative mortality in high

volume centres with high experience is around 5%, postoperative morbidity

remains an actual matter of concern. Postoperative complications can

occure in 40 to 80% of all patients (4). Prediction of the occurrence of a

major complication after esophagectomy with possible vital impact remains

an important tool for the medical team involved in the treatment of a

patient with esophageal cancer. The aim is the prevention and early

treatment of this complication and for the patients it gives an estimation of

the severity of the disease and of the surgical intervention. Late prognosis

for the patient diagnosed with esophageal cancer is reserved, in present

numerous researches are focused in studying the role of surgical treatment

in patients in which a neoadjuvant protocol has been performed.

GENERAL PART

This PhD Thesis containes a general part in which it was presented

the newest diagnostic and stadialisation methods, the general evaluation of

the patient, a part which included the prognostic scores used in esophageal

cancer surgery, a briefly and concise presentations of the most important

surgical interventions and of the protocols for radio and chemotherapy.

Also it was performed a meta-analysis of diagnostic studies for the

evaluation of sentinel lymph nodes in esophageal cancer.

In Chapter 1 there were presented general aspects regarding

epidemiology, risk factors for the two most frequent histological types:

scuamocellular tumours and adenocarcinomas; a small number of cases is

represented by the sarcomas, stromal tumours or nondiferentiated tumours.

In high risk areas such as Western Europe and Northern America smoking

and alcohol are encountered in more than 90% of scuamocellular tumours

(7). Other risk factors are: nutritional factors, pre-existent esophageal

conditions, Human papilloma virus infection, biphosphonates and personal

history of aero-digestive tumours. For adenocarcinomas main risk factors

are:gastroesophageal reflux disease, smoking, alcohol and obesity.

In Chapter 2 it was presented the diagnosis, stadialisation and

functional evaluation of a patient diagnosed with esophageal cancer. The

most important stadialisation tests are CT and echo endoscopy, and in

highly experienced centers the PET/CT. Those test are used on initial

evaluation and after the neoadjuvant protocol applied.

Chapter 3 describes the surgical treatment of esophageal cancer. In

this chapter were described insights regarding classical transthoracic and

transhiatal techniques. Due to the developed of minimally invasive

techniques and of the implementation of those techniques in esophageal

cancer surgery it were presented the outcomes of minimally invasive

esophagectomy. There is an increase frequency of minimally invasive

esophagectomy due to the low impact of surgery in a neoplasic patient with

an impaired nutritional status and who underwent a neoadjuvant protocol

treatment. The conversion rates vary between 0 to 29%, the most frequent

causes are: dense pleural adhesions, hemoragic accidents and the difficulty

in performing a intrathoracic anasthomosis (111). The results of the TIME

trial (Traditional Invasive versus Minimally Invasive Esophagectomy)

which represents the only prospective randomised study which compared

56 patients with minimally invasive esophagectomy with 59 patients with

clasic surgery showed a significantly lower pulmonary complications (29%

vs. 9%, RR 0.30 (0.12-0.76)). In this chapter were presented the early

postoperative outcomes in terms of mortality and morbidity. Recent data

reports mortality below 5% (157). Postoperative morbidity varies between

30-60% depending on the raportation accuracy, the most frequent

complications are respiratory (pneumonia, pleural effusion, respiratory

failure or empiema) between 20-40%. Late outcomes in term of survival

and reccurence are directly correlated with tumoral stage. 5-year survival

varies between 34-62% for I-IIA stages and drops to 17-25% for stage III

patients (163,164). Prognostic factors for survival are: complete resection,

ganglionar status, avoidance of postoperative complications and surgeon-

volume. The presence of residual disease in associated with a short survival

(165). Esophagectomy has a deep impact on quality of life. The decline of

physical status is due to the thoracotomy (chronic alteration of pulmonary

ventilation) or to the anatomical and functional alterations of digestion.

In Chapter 4 it was performed a meta-analysis of diagnostic

studies regarding the sentinel node concept in esophageal surgery. The

results of this meta-analysis show that sentinel nodes in esophageal cancer

have a wide distribution from the cervical to abdominal region bu with a

high incidence for the peritumoral nodes. The mean number of sentinel

lymph nodes varies between 2 to 4, which implies an extensive lymph node

sampling and an accurate intraoperative histopathology and

immunohystochemical evaluation. Based on the results of this study the

global accuracy for Tc99m and CT aided lymphography is around 90% (for

blue dye it was 79%), a value which can serve as a threshold for clinical

implementation (219). The results of this study showed that in present there

are inssuficient datas for clinical implementation of this method.

Chapter 5 is addressed to the radio and chemotherapy in

esophageal cancer. The combination between radio and chemotherapy was

investigated in randomised trials, the results leaded to the clinical

implementation of this method. This association increases the possibility of

a curative resection and gives a better local and distant control of the

disease (255). The radiotherapy or the chemotherapy alone as adjuvant

treatment remains controversial. Randomised studies (280-282) have not

showed an improved survival in patients in which postoperative

radiotherapy was performed. The only benefice was obtained in patients

with stage III tumours (282). The palliative surgical treatment it is not

considered a valid option for patients with locally advanced disease or

metastases, due to the short life expectancy and of the high postoperative

mortality and morbidity risks. Surgical by-pass can lead to a 50 to 60%

morbidity risk and mortality between 5 to 10 % (286). Endoscopic

palliation of dysphagia can be considered in the following situations:

patients with severe disphagia in which a definitive radiochemotherapy

protocol is planned, impossibility of palliation of dispgahia with non-

endoscopic methods, the recurrence of dysphagia after loco-regional

treatments, patients which are not candidates to radiotherapy.

PERSONAL CONTRIBUTIONS

CHAPTER 6. Evaluation of risk factors involved in the

occurence of postoperative complications after esophagectomy

Aim of this study was the evaluation of different prognostic scores

for the prediction of postoperative morbidity and mortality in a high

selectioned series of patients operated for esophageal cancer and

identification of specific risk factors for the occurrence of postoperative

severe morbidity. The secondary objective was the development and

validation of a new prognostic score for the occurrence of severe

complications after esophagectomy with special interest regarding the

nutritional status.

Material and methods

It was performed a retrospective study on a prospective collected

database which included all the patients diagnosed with esophageal cancer

in a single institution (Surgery Department of Veneto Oncologic Institute)

in which surgery was performed between January 2008 and October 2012.

There were included in the analysis patients with esophageal and

gasteoesophageal junctions Siewert Type I and II tumours.

All the patients underwent a standardised diagnosis and

stadialisation protocol which included: endoscopy with biopsy, echo-

endoscopy, high resolution CT scan of cervical, thoracic and abdominal

regions, PET/CT and laparoscopy. In all the patients a treatment protocol

was performed accordingly to a multidisciplinary meeting resolution.

Patients with tumours above T2N0 stage were considered suitable for a

neoadjuvant treatment protocol which consisted in a combination of radio

and chemotherapy. Surgical techniques were performed accordingly to

tumoral stage, functional status and tumour site.

Postoperative complications were graded after the Dindo-Clavien

scale (298) (Table 6.I) or CTC (Common Terminology Criteria of Adverse

Events). For each patient were calculated the physiologic and operative

score based on POSSUM scale as described in original article (89),

Charlson scale and nutritional status.

A logistic regression was performed in order to have a good

evaluation of each independent factor for the prediction of adverse

postoperative events. All statistical significant variables associated with the

occurrence of a postoperative complication were inserted in a stepwise

logistic regression model of a new estimation model. Those independent

prediction factors were used for the creation of a new prognostic score.

Table 6.XI. Postoperative complications

N 171

Mortality 3 (1.8%)

Overall morbidity 62 (36.3%)

Pulmonary complications 26

Cardiac complications 16

Fistula 10

Urinary 5

Sepsis 5

Postoperative hemorrhage 5

Other (wound, thoracic duct fistula) 8

Complications grading

Grade I-II (minor)

Grade III-IV (major)

39 (22.8%)

23 (13.5%)

Major complications

Pulmonary

Cardiac

Fistula

Bleeding

15

5

5

3

Data expressed as n (%)

Twenty-three patients (13.3%) developed a major complication

(according to Dindo-Clavien scale). By comparing the patients with a

major complication and those without or with a minor one, both

components of prognostic nutritional index (albumin, p=0.01 and

lymphocytes p=0.02) presented significantly lower values in patients with

major complications.

Moreover, patients with a severe complication had a higher

incidence of peripheral vascular disease (p=0.03), of cerebrovascular

diseases (p=0.03) and of previous history of gastric ulcer (p=0.08). Among

the components of the physiologic score of POSSUM, an abnormal pulse

(between 40-49 or 81-100), an impaired pulmonary function (dyspnoea on

mild exertion or mild chronic pulmonary disease) were encountered more

frequent in those patients (p=0.05, close to the significance level.

Table 6.XVI. Multivariate analysis of risk factors

P value Odds ratio (95% C.I. )

Neoadjuvant treatment 0.07 7.43 (0.84-65.88)

Albumin 0.04 0.89 (0.80-0.98)

Respiratory status 0.02 3.44 (1.19-9.95)

Abnormal pulse 0.0001 8.77 (2.91-26.44)

Tumour location 0.77 -

Hystological type 0.53 -

Lymphocites 0.23 -

Peripheral vascular disease 0.25 -

Gastric ulcer 0.42 -

Cerebrovascular disease 0.10 -

Figure 6.14. The new formula used for the estimation of the risk for developing a

severe complication after esophagectomy

Discussions

Cardio-pulmonary and nutritional status together with the

neoadjuvant treatment were independent associated with the occurrence of

a major complication post-esophagectomy. In the series of patients in this

study lower levels of albumin were encountered in patients with severe

complications, previous reports in the literature showed a threshold of 35

mg/dl for the occurrence of a major complication (309-311). Age was not

correlated with postoperative morbidity.

Identifying the subgroup of patients with a high risk for developing

a severe complication after esophagectomy plays an important role in the

selection of surgical candidates for esophagectomy, in the understanding of

the severity of the disease and of the surgical intervention. An improvement

of the current prognostic scores used in oncologic surgery can be made

through the introduction in the formulas for the calculation of different

physiological scores of a nutritional status coefficient and that the overall

estimated percentages must have a correction factor directly dependant to

the surgical volume of the hospital or of the surgical team.

CHAPTER 7. Minimally invasive esophagectomy for esophageal

cancer

The aim of this study was the evaluation of the advantages of

hybrid minimally invasive esophagectomy (laparoscopy and right

thoracotomy) for medium and lower thoracic esophageal cancer in terms of

early postoperative outcomes, immune response and performance status of

the patients.

Materials and methods. A retrospective study was performed

conducted on a prospective collected database which included all the

patients with esophageal cancer in which surgery was performed between

January 2008 and April 2013 in the Surgery Department of the Veneto

Institute of Oncology, Padova, Italy. Patients characteristics, type of

surgery and early outcomes were compared between patients in which

hybrid minimally invasive esophagectomy was performed and those in

which classical surgery was done. Due to the high heterogeneity a subgroup

analysis was performed, a case-control study. The match criteria for the

case-control study were: sex, age, tumour site, histological type, stage and

the neoadjuvant treatment protocol.

The parameters of the immune response included in the analysis

were: dynamics of the white blood cells, C reactive protein and albumin in

the first, third and seventh postoperative day. Functional status of the

patients was assessed by the Barthell scale (functional scale which

evaluates the daily activity) (325).

Results

During January 2008 and April 2013 surgery was performed on

194 patients with esophageal cancer. Patients’ characteristics are showed in

Table 7.I.

Tabel 7.I. Patients characteristics

Total (N=194) HMIE (N=37) Open (N=157) p

Age 60.706 (59.066-

62.346)

57.378 (53.03-

61.71)

61.49 (59.73-

63.24)

0.0518

Sex M/F 155/39

Physiologic

score

15.79 (15.34-

16.24)

15.03 (14.28-

15.78)

15.94 (15.43-

16.46)

0.13

Charlson score 2.69 (2.559-

2.832)

2 (2-3)

2.59 (2.3-2.88) 2.71 (2.56-

2.87)

0.47

Age adjusted

Charlson score

5. 026 (4.798-

5.253)

5 (5-5)

4.51 (4.04-

4.98)

5.14 (4.88-5.4) 0.03

ASA

1

2

3

93 (47.9%)

90 (45.6%)

11 (5.67%)

15 (40.54%)

21 (56.75%)

1 (2.7%)

78 (49.68%)

69 (43.94%)

10 (6.36%)

0.61

Commorbidities

Pulmonary 26 (13.4%) 4 (10.8%) 24 (15.28%) 0.031

Myocardial

infarction

16 (8.24%) 2 (5.4%) 14 (8.91%) 0.026

Arteriopathy 13 (6.7%) 2 (5.4%) 11 (7%) 0.001

Peptic ulcer 14 (7.21%) 1 (2.7%) 13 (8.2%) 0.059

Chronic liver 15 (7.7%) 4 (10.8%) 11 (7%) 0.03

Neurologic 12 (6.1%) 2 (5.4%) 10 (6.36%) 0.67

Diabetes 13 (6.7%) 1 (2.7%) 12 (7.64%) 0.051

Connective

tissue disease

9 (4.63%) 2 (5.4%) 7 (4.45%) 0.014

Limphoma 3 (1.5%) 2 (5.4%) 1 (0.006%) 0.009

Renal disease 1 (0.005%) 0 1 (0.006%) -

Datas expressed as mean/median with confidence intervals

Table 7.VI. Patients characteristics in the case-control study

HMIE Open P

Age 58.28 (53.89-62.68) 62.28 (58.35-66.2) 0.17

Previous history

Cardiac disease 5 (13.51%) 7 (18.9%) 0.76

Pulmonary disease 5 (13.51%) 6 (16.2%) 0.88

Arteriopathy 2 (5.4%) 2 (5.4%) -

Peptic ulcer 0 3 (8.1%) 0.20

Chronic liver 3 (8.1%) 3 (8.1%) -

Diabetes 1 (2.7%) 3 (8.1%) 0.07

Charlson score 2.51 (2.23-2.79) 2.68 (2.33-3.03) 0.42

Age adjusted Charlson

score

4.45 (3.96-4.94) 5.15 (4.68-5.62) 0.04

Physiologic score 15.2 (14.4-16) 16.5 (15-18) 0.12

BMI 24.54 (22.97-26.12) 23.88 (22.17-

25.58)

0.55

Weight loss 4.47 (2.5-6.4) 4.31 (2.49-6.13) 0.9

Percentage weight loss 8.4 (5.24-11.56) 7.15 (4.73-9.57) 0.53

Hb 13.26 (12.73-13.78) 12.39 (11.73-

13.05)

0.03

WBC 6365 (5596-7135) 6287 (5560-7013) 0.88

Lymphocites 1402 (1220-1584) 1303 (1114-1491) 0.44

Albumine levels 42.74 (41.61-43.84) 41.15 (39.32-

42.98)

0.13

Total proteins 72 (70.5-73.65) 70.2 (66.9-73.5) 0.28

CA 19-9 16.91 (5.96-27.87) 16.36 (9.86-22.85) 0.93

AFP 4.67 (2.19-7.16) 4.55 (2.14-6.96) 0.94

ACE 3.01 (1.9-4.12) 4.71 (2.33- 7.09) 0.17

Tabel 7.VII . Parametrii studiați la lotul caz-control

MIE open p

CRP day 1 67.36 (59.15-75.57) 91.83 (79.39-104.28) 0.0013

CRP day 3 113.1 (95.7-130.6) 143.9 (127.48-

160.37) 0.011

CRP day 7 45.76 (30.75-60.79) 55.05 (38.67-71.41) 0.39

Alb day 1 31.05 (29.53-32.56) 27.22 (25.85-28.58) 0.0003

Alb day 3 28.91 (28-29.82) 27.13 (26.13-28.13) 0.0096

Alb day 7 29.5 (28.6-30.39) 27.82 (26.3-29.35) 0.043

WBC day 1 8978 (8044-9913) 10230 (9231-11230) 0.067

WBC day 3 9091 (8306-9877) 9591 (8696-10485) 0.39

WBC day 7 7785 (7137-8434) 8235 (7169-9300) 0.46

Barthell admision 98.37 (97.13-99.62) 99.45 (98.8-100) 0.12

Barthell intermediary 17 (13.5-20.5) 7 (5.1-8.9) <0.0001

Barthell dismission 97.5 (96.1-99) 84.8 (82.5-97.5) 0.005

CRP- C reactive protein, Alb-albumine, WBC- white blood cells

Figure 7.9. Dynamics of the C reactive protein

Figure 7.10. Dynamics of the albumine levels

Figure 7.11. Dynamics of the white blood cells

HMIE

0

1

Means (error bars: 95% CI for mean)

180

160

140

120

100

80

60

40

20

CRP_z_1 CRP_z_3 CRP_z_7

MIE

0

1

Means (error bars: 95% CI for mean)

33

32

31

30

29

28

27

26

25

ALB_z_1 ALB_z_3 ALB_z_7

MIE

0

1

Means (error bars: 95% CI for mean)

11500

11000

10500

10000

9500

9000

8500

8000

7500

7000

WBC_z_1 WBC_z_3 WBC_z_7

Table 7.VIII . Pathological specimen and surgery characteristics

MIE open p

Total number lymph

nodes

23.08 (20.65-35.5) 24.05 (21.05-27.05) 0.61

Abdominal lymph

nodes

11.08 (10.05-12.1) 10.45 (9.51-11.4) 0.36

Lenght surgery 425 (382-467) 378 (33-422) 0.11

Blood loss 161 (134-189) 204 (164-244) 0.07

Hospital stay 15.9 (13.5-18.2) 16.6 (14.7-18.5) 0.61

ICU stay 2 (1.4-2.6) 2.7 (2.3-3.1) 0.06

Tabel 7.X. Multivariate analysis of factors for postoperative morbidity

P value on

univariate

analysis

Odds Ratio Confidence interval

95%

Albumine 0.007 0.4211

Lymphocites 0.039 0.9958

Prognostic

nutritional index

0.002 2.1545

Cardiac pathology 0.058 1.3839 0.3716- 5.1534

Arteriopathy 0.001 4.4439 0.8130- 24.2913

Pulmonary

conditions

0.09 1.3609 0.5075- 3.6924

Physiologic score 0.005 1.0944 0.9542- 1.2553

Charlson score 0.014 1.4272 0.8368- 2.4340

Age adjusted

Charlson score

0.030 1.8879 0.6276- 1.2562

Minimally invasive

technique

0.7680 0.4368- 4.2321

Discussions

The results of this study showed that there were no differences in

terms of patients’ characteristics when comparing all the patients. The

patients had the same physiological score of POSSUM, Charlson score and

ASA scale. Those prognostic scores represent different modalities of

general status assessment: from a subjective evaluation in ASA scale (331)

to an detailed evaluation in physiologic score. Patients in which

laparoscopy was performed presented significantly lower incidences of

pulmonary, cardiac, chronic peripheral vascular disease and chronic liver

diseases. This fact can be explained by the inclusion criteria for

laparoscopy, this technique has a limited indication in patients with severe

alteration of cardiac and pulmonary functions.

The analysis of immune status indicators (CRP) showed a

significantly lower values for the first 24 and 72 hours after surgery. Those

values can be explained through a blockage of the neuronal and

inflammatory from the level of the peritoneum, through the absence of the

abdominal wall and peritoneal incision and this can reduce the

neurohormonal stress response and can improve the recovery after surgery

(332). Another explication can be the CO2 pneumoperitoneum and limited

dissection of the abdominal organs (333,334). The dynamics of CRP after

laparoscopic surgery was demonstrated for gastric cancer (335), colorectal

cancer (336, 337) or pancreatic cancer (338) and also for laparoscopic

resection for benign conditions (339).

By performing a case-control study with strict inclusion parameters it was

limited the effect of other factors that could impair the immune response.

Another indicator of the immune response was the dynamics of the white

blood cells, those presented significantly lower values only in the first

postoperative day, at the 3rd

and 7th postoperative day the values showed no

difference. This was also assessed in another study that compared 17

patients with transhiatal esophagectomy with a similar group with

laparoscopy (340). The two groups in the case-control study presented

significantly different functional status on the 3rd

and 7th postoperative day.

Although statistical significant, the functional status was impaired at the 3rd

postoperative day due to the effect of the thoracotomy. In the 7th

postoperative day patients with hybrid minimally invasive esophagectomy

presented an improved motor functions with a high degree of autonomy.

Unipulmonary ventilation during thoracotomy leads to mechanical,

hydrostatic and inflammatory lesions known as ventilation induced lesions

(341). The ventilated lung receives all the blood and this combined with the

ventilation pressure and the increased hydrostatic pressure leads to diffuse

endothelial injuries. After the reexpansion of the lung the inflammatory

mediators can induce reperfusion lesions. Endothelial injury induces a lack

of response of the pulmonary vessels (342). Laparoscopy can prevent and

can limit the extent of this process through a limited muscular trauma, a

reduced postoperative pain, a limited mechanical dysfunction and through a

limited immune response (344). By combining the laparoscopy and

thoracotomy in the treatment of esophageal cancer it is believed that a

limited immune response can be obtained which can have a protective

effect for severe complications without compromising the oncological

standards.

CHAPTER 8. Survival analysis in patients operated for

esophageal cancer based on the response of neoadjuvant

treatment

Aim of the study

Esophageal cancer is one of the most lethal disease with 5 year

survival rates between 15 to 39% in patients with locally advanced disease

in which a neoadjuvant protocol has been done (345). Esophagectomy

represents the standard treatment for resectable tumours (346) and can offer

a limited (25 to 35%) cure rates (91). The combination of radio-

chemotherapy and surgery can give a survival benefice in patient who

presented a good response to neoadjuvant treatment (245,347). For the

patients in which only surgery was performed the best prediction factor for

survival is the TNM stage (352).

The aim of this study was to analyse the factors associated with

long term survival and disease free interval in patients operated for

esophageal cancer. The secondary aim was survival analysis for patients in

which palliative treatment was performed.

Material and methods

A retrospective study has been conducted on a prospective

collected database of the Veneto Oncology Institute Padova, Italy. This

database included all the patients diagnosed with esophageal cancer in all

the surgery departments. Study period was January 2000 to December 2009

(10 years) in order to have an accurate evaluation of all the patients. All the

patients were initially evaluated through endoscopy with biopsy and the

stadialisation protocol included: CT scan of the cervical, thoracic and

abdominal regions, echo-endoscopy and cervical echography (for upper

thoracic and cervical localisations). The PET/CT was not systematically

used in all the patients. After initial evaluation all the patients were staged

accordingly to the TNM classification of the AJCC, patients with locally

advanced tumours have been submitted to a neoadjuvant treatment protocol

which consisted in radio and/or chemotherapy. We included in the analysis

patients with celiac lymph nodes metastases (M1a) because all those lymph

nodes were resected in patients which surgery was performed (standard 2

field lymphadenectomy).

In order to have a good clinical evaluation of the effect of the neoadjuvant

treatment on survival, patients with a partial clinical response were divided

in two groups:

- Patients with a good partial clinical response: patients who initially

were T3N1 and became T1N1 or T1N1 , T2N1 and became T1N0

or T0N1

- Patients with a poor partial clinical response: patients who initially

were T3N1 and became T3N0, T2N1 to T1N1 or T2N0

It was analysed global survival in patients in which palliative treatment

was performed. A subgroup analysis was performed for histological types

and stages. In resected patients global survival was assessed according to

tumour stage, histology, neoadjuvant treatment, and the response to the

neoadjuvant treatment.

Results

Table 8.II. Tumour characteristics on diagnosis

ADK SCC Total

N 369 582 951

Site:

cervical

upper thoracic

medium thoracic

lower thoracic

gastroesophageal juntion

4 (1.1)

9 (2.4)

10 (2.7)

131 (35.5)

215 (58.3)

85 (14.6)

164 (28.2)

206 (35.4)

123 (21.1)

4 (0.7)

89 (9.4)

173 (18.2)

216 (22.7)

254 (26.7)

219 (23.0)

Clinical T stage

is

1

2

3

4

10 (2.7)

45 (12.2)

49 (13.3)

230 (62.3)

35 (9.5)

6 (1.0)

45 (7.8)

77 (13.2)

308 (52.9)

146 (25.1)

16 (1.7)

90 (9.5)

126 (13.2)

538 (56.6)

181 (19.0)

Clinical N stage

0

1

118 (32.0)

251 (68.0)

149 (25.6)

433 (74.4)

267 (28.1)

684 (71.9)

Clinical M stage

0

1lymph.

351 (95.1)

18 (4.9)

552 (94.9)

30 (5.1)

903 (95.0)

48 (5.0)

Data expressed as n(%) or *median (confidence interval).

°data not available for 2 patients

Figure 8.1. Patients selection

Table 8.IV. Neoadjuvant tratment applied for all the patients

ADK SCC Total

N 369 582 951

Neoadjuvant tratment:

No

Chemotherapy

Radiotherapy

Chemo-radiotherapy

222 (60.1)

49 (13.3)

4 (1.1)

94 (25.5)

200 (34.4)

48 (8.2)

10 (1.7)

324 (55.7)

422 (44.4)

97 (10.2)

14 (1.5)

418 (43.9)

Chemotherapy association:

2000-2009

Patients with esophageal or gastroesophageal junction tumours

1142

Site: cervical, thoracic or gastroesophageal junction

1120

Histology: scuamocelular or adenocarcinoma

1075

Clinical M1 or Mx

124

Patients analysed

Surgery

N=626

Palliation

n=140

Definitive RCT

N=186

Other types:

45

Other:

22

DDP

DDP+5FU

Other

0

6

43

2

30

16

2

36

59

Radiotherapy:

External beam radiotherapy

Brachytherapy

Both

3

0

1

5

2

3

8

2

4

Chemo-radiotherapy:

DDP+RT

DDP+5FU+RT

Other

5

41

48

13

223

88

18

264

136

Data expressed as (%).

Table8.XII. Metastatic lymph nodes according to tumoral site

Tumour site

Cervical Upper

thoracic

Medium

thoracic

Lower

thoracic

GEJ

N 38 79 143 185 181

Metastatic lymph nodes:

Cervical 3 2 1 1 1

Supraclavicular 0 2 3 1 0

Paraesofagian 2 9 19 52 48

Paratracheal 2 4 6 8 5

Subcarinal 0 4 8 10 11

Recurrențial 2 10 9 4 5

Lower pulmonay

vein

0 0 3 7 6

Paracardial 1 6 17 30 63

Perigastric 0 10 18 48 61

Celiac 0 3 12 26 38

Data expressed as n.

Figure 8.6. Global survival according to TNM stage on resected patients

Figure 8.8. Disease free interval according to tumoral stage

0

20

40

60

80

100

0 12 24 36 48 60

Glo

bal

surv

ival

(%)

Months from diagnosis

p<0.0001

pStage 0

pStage I

pStage II

pStage III

pStage IV

0102030405060708090

100

0 12 24 36 48 60Dis

ease

fre

e in

terv

al

(%)

Months from surgery

p<0.0001

pStage 0

pStage I

pStage II

pStage III

pStage IV

CR – complete response, PR – partial response, NC – non responders, PD – progresive disease

Figure 8.9. Global survival based on clinical response to neoadjuvant therapy

Due to the fact that it was observed a signifficant diference of the

survival curves and of the 5 years survival in patients who presented a

complete response and those with partial response, and of the

nonresponders and those with partial response, patients with partial

response were divided in two subgroups according to the criterias described

in the material and methods chapter. Survival analysis and disease free

interval are shown in Figure 8.11 and 8.12.

Figure 8.10. Disease free interval according to clinical response to neoadjuvant

therapy

0

20

40

60

80

100

0 12 24 36 48 60

Glo

bal

surv

ival

(%)

Months from diagnosis

p<0.0001

CR

PR

NC

PD

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Dis

ease

fre

e in

terv

al

(%)

Months form surgery

p=0.001

CR

PR

PD

NC

Figure 8.11. Global survival according to the new classification of clinical

response to neoadjuvant treatment

Patients with a good partial response presented a statistical

significant improved survival when compared with patients with a poor

clinical partial response (p<0.0001), the survival curves for the last group

are relatively similar to those of patients with no response to treatment.

Patients who were no responders to neoadjuvant treatment and in which

surgery was performed presented survival curves similars to patients with

progressive disease.

Figure 8.12. Disease free interval according to the new classification of clinical

response to neoadjuvant treatment

0102030405060708090

100

0 12 24 36 48 60

Glo

bal

surv

ival

(%)

Months form diagnosis

p<0.0001

CR

PR+

PR

NC

PD

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Dis

ease

fre

e in

terv

al

(%)

Months from surgery

p=0.003

CR

PR+

PR

NC

PD

On univariate analysis, independent factors directly associated with

5-years survival were : age (as a continuous variable), ASA scale (I-II vs.

III-IV, p=0.02), chronic pulmonary disease (p=0.002), type of surgical

resection (p<0.0001), neoadjuvant treatment (p<0.0001) and postoperative

morbidity (p=0.003). Histological type, tumoral site or the extent of

lymphadenectomy were not correlated with long term survival.

Multivariate analysis of survival showed that resection type (HR

0.5 (0.33-0.76), p=0.04), TNM stage (stage II HR 2.00 (1.30-3.08),

p=0.002; stage III HR 3.44 (2.10-5.63), p<0.0001; stage IV HR 3.81 (2.25-

5.63), p<0.0001) and postoperative morbidity (HR 1.42 (1.10-1.84),

p=0.008) were correlated with long term survival.

For the disease free interval, independent factors were:neadjuvant

treatment (p=0.004), type of resection (p<0.0001), TNM stage (p<0.0001).

Hystological type, tumoral site, extent of lymphadenectomy and

postoperative morbidity did not influenced the disease free interval. On

multivariate analysis, neoadjuvant treatment neoadjuvant (HR 1.85 (1.37-

2.50), p<0.0001), type of resection (HR 0.43 (0.27-0.68), p=0.0003), lymph

node metastases (HR 2.45 (1.77-3.40), p<0.0001) and postoperative

adjuvant treatment (HR 1.57 (1.10-2.24), p=0.01) have influenced disease

free interval.

Discussions

The global 5-years survival was 49%, with a median survival of 52

months. These values can be explained by the fact that in the analysis were

included patients with early tumours (stage I and II) in which neoadjuvant

treatment was not performed. Global survival analysis for the two

histological groups showed that the two survival curves are similar there is

slight non-significant difference at 3 years (52% for scuamocellular

tumours and 63% for adenocarcinomas). Neoadjuvant treatment induces a

survival benefice for adenocarcinomas , but with a similar 5-year survival.

In resected patients alive at 5 years recurrence occurred in 42%. The most

frequent site was systemic 60%, lymphonodal (30%) or both (10%).

Survival curve analysis based on the response to neoadjuvant

treatment showed that the best survival was seen in patients with complete

response. At 12 months survival of the patients with complete response and

those with partial response was similar, but it was statistical significant

different at 2 and 5 years. Moreover, patients without clinical response or

with progressive disease after induction therapy had similar 5-years

survival, but with survival curves that were different. At 5 years patients

with partial response presented an intermediary survival between those

with complete response and those with stable disease. The median survival

for patients with partial response was 5 years, 2 years for non-responders

and 20 months for patients with progressive disease that were resected.

Relatively similar results were obtained for disease free intervals,

this was similar in patients with progressive disease and patients without

response, but it was different in patients with complete response and partial

response. It can be considered that 3 years after resection a patients has low

chances of recurrence.

Choosing the best candidate for multimodal treatment in

esophageal cancer represents a difficult task. When considered the

morbidity of surgical and neoadjuvant treatment, surgery must be

performed only in the subgroup of patients in which the best survival

benefice can be obtained. The best results are obtained in patients with a

good response to neoadjuvant treatment.

CHAPTER 9. Comparative study regarding early postoperative

outcomes based on surgical approach for esophagectomy

Aim of the study

Tailoring the best approach in esophageal cancer depends on the

level of expertise of the surgical team involved in the treatment, the two

most utilised techniques are transthoracic with cervical or mediastinal

anastomosis and transhiatal. The aim of this study was the assessment of

each prognostic score to predict the postoperative morbidity and the

evaluation of postoperative early results in terms of mortality and morbidity

based on surgical approach (transthoracic or transhiatal).

Materials and methods

A retrospective study conducted on a prospective collected

database which included all the patients operated for esophageal cancer

between January 2004 and March 2013 in the 3rd Surgical Unit of the “Sf.

Spiridon ” Hospital and the 1st Surgical Unit of the Regional Institute of

Oncology Iași was performed. Patients comorbidities were assessed

according to the Charlson scale and age adjusted Charlson scale:

hypertension, cardiac disfunction (previous history of ischemic disease,

angina, cardiac failure or atrial fibrilation), pulmonary disfunction

(FEV1<70%, vital capacity<80%), peripheral vascular disease,

neurological disfunction (previous history of stroke, transient stroke,

epilepsy or Parkinson disease), hepatic cirrhosis, chronic renal disease,

diabetes. In order to have a better evaluation of the functional status it was

calculated the physiological score of the POSSUM. Observed and predicted

values for mortality and morbidity were compared. The performance of

each prognostic score was compared in terms of discrimination as area

under the ROC curve and calibration. An area under ROC curve below 0.70

was considered to be a poor discriminatory power, areas between 0.70 and

0.80 a medium power and areas over 0.80 a good discriminatory power.

A uni and multivariate analysis was performed in order to identify

the predictors for postoperative morbidity after esophagectomy.

Results

During January 2004 and March 2013 137 patients were diagnosed

with esophageal cancer, in which surgery was performed in 50 cases.

Table 9.II. Patients characteristics

Total

(N=50)

TTE

(N=33)

THE (N=17) P value

Tumour site

Medium thoracic

Lower thoracic

26 (52%)

24 (48%)

23 (69.7%)

10 (30.3%)

3 (17.6%)

14 (82.4%)

0.0007

Histology

SCC

ADK

36 (72%)

14 (28%)

26 (78.8%)

7 (21.2%)

10 (58.8%)

7 (41.2%)

0.18

Stage

1

2

3

7 (14%)

17 (34%)

26 (52%)

3 (9%)

13 (39.5%)

17 (51.5%)

4 (23.5%)

4 (23.5%)

9 (53%)

0.67

Organ replacement

Gastric

Colon

44 (88%)

6 (12%)

29 (87.9%)

4 (12.1%)

15 (88.2%)

2 (11.8%)

0.85

Tabel 9.III. Early postoperative outcomes

Total N=50 TTE N=33 THE N=17 P value

Global morbidity 30 (60%) 20 (60.6%) 10 (58.8%) 1

Pulmonary 23 (46%) 15 (45.4%) 8 (47%) 1

Cardiac 5 (10%) 4 (12.1%) 1 (5.9%) 0.64

Fistula 6 (12%) 4 (12.1%) 2 (11.8%) 0.99

Bleeding 5 (10%) 3 (9.1%) 2 (11.8%) 0.99

Neurologic 2 (4%) 1 (3%) 1 (5.9%) 0.99

Hepatic failure 1 (2%) 1 (3%) - -

Sepsis 10 (20%) 8 (24.2%) 2 (11.8%) 0.46

Recurrent injury 6 (12%) 2 (6%) 5 (29.4%) 0.037

Minor

complications

18 (36%) 12 (36.3%) 6 (35.2%) 0.95

Major complications 15 (30%) 11 (33.3%) 4 (23.5%) 0.53

Mortality 5 (10%) 4 (12.1%) 1 (5.9%) 0.64

ICU stay 6 (5-7) 6 (5-7) 6 (4.6-8.8) 0.70

hospitalisation 14 (12-16) 14 (12-17.4) 14 (10.6-

20.2)

0.81

Table 9.IV. Comparative analysis of patients characteristics based on the

occrurrence of a complication

Complications Without P

value

OR

Charlson score 3 (2-4) 2.5 (2-3) 0.23

Age adjusted

Charlson score

5 (4-6) 3.5 (3-4) 0.009 1.4(0.6347 -

3.0901)

Physiologic score 17 (14-19) 15 (14-15) 0.007 1.4415 (0.9726 -

2.1366)

Operative score 17 (17-19) 17 (17-18) 0.23

ASA II/III 15/10 15/3 0.17

Age 63 (57.3-68.5) 56 (51-

58.3) 0.006 1.0128 (0.8803 -

1.1653)

Hb 11.3 (10.6-13) 11.7 (10.7-

14)

0.5

Neoadjuvant

treatment

13 (52%) 8 (44%) 0.75

Toracotomy 17 (68%) 11 (50%) 0.75

Histology

(SCC/ADK)

22/3 12/6 0.13

The discriminatory ability for each prognostic score was presented

in Table 9.V.The area under ROC curve for operative score and Charlson

score showed a low discriminatory power. Physiological score of POSSUM

and age adjusted Charlson scale and age as an independent factor showed a

good discriminatory power. The best predictive performance was for

POSSUM which had the largest area under ROC curve (0.826; 95% CI,

0.67 – 0.92)

Table 9.VI. Uni and multivariate analysis for predictors of morbidity

Valoare p Odds Ratio 95% CI

Age adjusted Charlson score 0.028 2.7772 1.1140 - 6.9236

Charlson score 0.139 0.3491 0.0865 - 1.4090

ASA 0.60 1.7347 0.2202 - 13.6674

Physiologic score POSSUM 0.0033 1.7601 1.2067 – 2.5674

Toracotomy 0.80 1.2469 1.2067 – 2.5674

Tumour site 0.5619 0.6258 0.1284 - 3.0504

Discussions

Based on the results of this study, esophageal cancer presented a

low resecability rate (29.25%), two major causes leaded to this result: poor

general performance of the patients and locally advanced tumours on

diagnosis. Cardiac and pulmonary comorbidities were the two leadind

factors that impaired resectability. Although all the patients underwent a

thorough functional evaluation previous to surgery, there was not

calculated any preoperative prediction score, the only evaluation was made

using the ASA scale. The results of this study shows that all the predictive

scores (Charlson and age adjusted Charlson score, physiological score

POSSUM, ASA scale) were significantly different in patients with different

approach. This can be explained by the selection of the patient suitable for

thoracotomy, this approach was not performed in a patient with severe

alteration of cardiac and pulmonary function. The observed mortality in

this series was best predicted by the POSSUM score the results were

included in the confidence interval with an observed/predicted ratio of 1.1.

previous studies that validated POSSUM score showed ratios between 0.37

and 0.66 (304,313) and 0.29 and 0.71 (303,305,313,316) for O-POSSUM.

CHAPTER 10. Final discussions and conclusions

There is a continuous debate regarding the management of a patient

with esophageal cancer: choosing the best approach, the extent of resection,

the proper lymphadenectomy, and the anastomotic site. An accurate staging

can select the best treatment plan for a newly diagnosed patient with

esophageal cancer, the accurate evaluation of metastatic disease and the

identification of the subgroup of patients with locally advanced tumours

that can benefit from the neoadjuvant treatment. When surgery can be

performed, this is preferred to be done in a tertiary centre with a highly

trained team involved in management of a patient with esophageal cancer.

Although surgery remains the mainstream treatment for esophageal cancer

long time prognosis remains poor, with the exception of early stages of the

disease. Therefore there should be an individualisation of treatment for

each patient in order to obtain the best results.

In Chapter 9, entitled “Comparative study regarding early

postoperative outcomes based on surgical approach for

esophagectomy” it were evaluated datas regarding mortality and

morbidity after esophagectomy in 50 patients on a 10 years period. This

study included a heterogenous series of patients, although most of the

patients were diagnosed with locally advanced tumours, the neoadjuvant

treatment protocol was not applied in all the patients. Newly diagnosed

patients with esophageal cancer presented a poor resectability rate due to

the presence of severe comorbidities or of locally advanced/metastatic

lesions. The most frequent cases for non-resectability were the cardiac and

pulmonary disfunctions. Moreover, in patients with an impaired pulmonary

function, the thoracotomy was avoided, being preferred the transhiatal

approach. All patients who presented an alteration of the preoperative

functional test developed a severe postoperative complications and death

occurred in 2 cases. Global 30 days mortality was 10%. One possible

explanation can be the extent of surgery on a frail patient with a poor

functional reserve.

The results of the study showed that there was no difference in

terms of pulmonary complications, but it can not be considered that

thoracotomy does not increase the risk of pulmonary complications. It can

be concluded that tailoring the best approach can lead to similar results in

this term. For all the patients it was not performed a standardised

evaluation of functional status, only prognostic scale used was ASA scale.

All the others prognostic scores were retrospective calculated.

Although in all the patients surgery was performed in two highly

specialised centres by a highly experienced team, the postoperative results

can not be compared with those of other centers highly experienced in the

management of esophageal cancer. There was no standardised protocol of

multimodal treatment for the patients in our series. Postoperative follow-up

was not complete and the lack of data did not permitted an accurate

survival, quality of life analysis.

During my doctoral studies period I was the beneficiary of a

doctoral fellowship bourse in a highly experienced centre focused on

esophageal cancer (Veneto Institute of Oncology, Padova, Italy). During

this period several studies were performed using a prospective collected

database.

In Chapter 6 it was designed a study in which it was tested the

ability of different prognostic scores for the prediction of postoperative

mortality and morbidity after esophagectomy, and the creation of a novel

score that presents a better estimation of this effect. Esophageal cancer can

lead to a severe alteration of the nutritional status and the influence of

malnutrition on postoperative complications was studied.

In order to limit the selection bias the selection period was limited

to 5 years, all the patients underwent a standardised stadialisation and

multimodal treatment protocol. Surgery and postoperative treatment was

also performed under strict regulations. All the postoperative complications

were uniformly graded according to the therapeutic consequences. In a

series of 171 patients the predictive capacity for severe morbidity was

tested for: POSSUM score and its derivates, Charlson and age adjusted

Charlson score , ASA score. Nutritional status indicators were albumin,

prealbumine, total proteins , lymphocytes , BMI and weight loss.

Cardiopulmonary and nutritional status and neoadjuvant treatment

were associated with the occurrence of a postoperative complication. There

was no correlation between weigh loss or BMI and postoperative

complications. This result demonstrates that a patient can suffer form

malnutrition even on low percentages of weight loss with an direct impact

on postoperative course. Patients with severe complications presented

significantly lower levels of albumin and lymphocytes. Prealbumine, as an

indicator of the short term nutritional status was not correlated with the

occurrence of a complication.

Patients age was not associated with a higher risk of complications

and it can not be considered a limiting factor for esophagectomy. The

prognostic risk score analysis showed that all the scores had a limited

predictive ability, and this was the reason why, using logistic regression a

novel prognostic score was created which included one indicator of the

nutritional status. The combination of neoadjuvant treatment, albumin

levels, pulmonary and cardiac status has the best predictive ability.

Due to the high rates of mortality and morbidity and with the

development of minimally invasive techniques esophagectomy can be

performed using this technique. The impact of minimally-invasive surgery

on postoperative course after esophagectomy was previous studied in

several restrospective studies. In the study described in Chapter 7 it was

analysed the impact of minimally-invasive techniques on immune response

by performing the abdominal part of the intervention through laparoscopy

(hybrid minimally invasive esophagectomy). It was performed a case-

control study that compared 37 patients in which hybrid esophagectomy

was performed with 37 patients conventional operated. The selection

criterias for the case-control study were: age, sex, stage, tumour site and the

neoadjuvant treatment.

The results of this study showed that the levels of C reactive

protein had a different dynamics, with lower levels at 27 and 72 hours after

minimally invasive techniques. The white blood cells number was lower

only in the first 24 hours after surgery. Those results can be explained by

the neuronal blockage from the level of abdominal wall peritoneum, the

absence of abdominal wall incision and the reduced neuro-hormonal stress

response. Another explanation can be the limited dissection using

laparoscopy. Patients with laparoscopy presented higher levels of albumin

during the all postoperative period, and this can be explained by a normal

hepatic synthesis due to the low flow of inflammatory molecules form the

abdominal viscera. Patients operated laparoscopically presented an

improved functional recovery in the 3rd

and 7th postoperative day. One

week after surgery those patients presented improved motor functions with

a high degree of autonomy.

Laparoscopy can have a protective effect by reducing the muscular

trauma, lower pain levels, a lower limitation of ventilation and a reduced

immune response to trauma. The combination of laparoscopy and

thoracotomy can lead to a reduced immune response with a protective

effect on the occurrence of postoperative morbidity without compromising

the oncological principles.

The aim of the study in Chapter 8 was the evaluation of late

postoperative outcomes (survival and disease free interval) for patients in

which a neoadjuvant treatment was performed and were resected, based on

the evauation of response to neoadjuvance on restaging. Secondary

objectives were the survival in patients where a palliative treatment was

performed. On a series of 626 patients, neoadjuvant treatment was

performed in 55.62% cases, with a complete response rate of 26.2%. the

sensibility of diagnostic test on restaging showed a limited predictability

for tumour and lymph node status. (overall sensibility 54.6%, 61.66% and

specificity 69.39%). The analysis on lymph node metastases localisation

based on primary tumour localisation showed that primary are located in

the peritumoral region but with a non neglected percentage in distance site

locations. The percentage of celiac lymph node involvement increased with

the distal localisation of the tumour. Overall morbidity was 36.9%, with

statistically significant differences between the two major hystologic type

(patients with scuamocellular tumors developed more frequent a

complication).

Overall 5-years survival for patients in which a palliative treatment

was performed (surgery, endoscopy or radio-chemotherapy) was 3%,

patients that were still alive at 5 years were the patients with a clinical

complete response in which surgery was not performed. The median

survival for those patients was 10 months, at 2 years most of the patients

were deceased.

Survival curve analysis in patients who underwent neoadjuvant

treatment and were resected showed that the best survival was obtained in

patients with a complete clinical response. At 12 months survival of the

patients with complete response was similar with those with a partial

response and in was different at 2 and 5 years. Moreover, patients without

response or with progressive disease presented similar survival curves. 5

years survival for patients with partial response was intermediary. Median

survival was 5 years for patients with partial response, 2 years for patients

without response and 20 months for patients with progressive disease.

Disease free interval was relatively similar as survival, it can be concluded

that a patient can be considered of having small chances of recurrence 3

years after resection.

On the series of patients submitted to survival analysis by dividing

the subgroup of patients who presented a partial response to neoadjuvant

treatment in two subgroups it was shown that patients with a poor partial

response presented a survival similar to patients without response and

patients with a good partial response presented survival curves close to

those with a complete clinical response. For those, 50 % of all deaths occur

in the first 18 months from surgery. Although statistically significant, the

disease free interval presented relatively similar curves as survival. On

univariate analysis age and functional status (according to ASA scale) were

associated with survival but this association was not encountered for

multivariate analysis. Lymfonodal status, tumoral stage and postoperative

course were independent prediction factors for survival.

Choosing the best candidate for surgical resection after neoadjuvant

treatment in esophageal cancer can be difficult. Surgery must be performed

in the group of patients in where a prolonged survival can be obtained. The

evaluation of the effect of neoadjuvant treatment in terms of downstaging

and downsizing can be a good clinical tool in term of patient selection.

Final conclusions:

1. Surgical treatment of patients with esophageal cancer tends to

be done in high experienced centers, in order to give the

patient the best results on short and long term

2. An important role in patient selection for surgery plays the

identification of that subgroup of patients at high risk for the

development of a severe postoperative complication

3. Long term benefice of a patient who underwent an uneventful

postoperative course in a prologue survival

4. Nutritional status indicators can be utilised for the calculation

of a prognostic score prior to surgery; the prognostic score

designed in this thesis needs to be validated on large series of

patients

5. Minimally-invasive techniques can safely be used in

esophageal cancer surgery, without compromising the

oncological principles, the immediate consequences are a

faster recovery with a diminished immune response to

surgery

6. The advantages of minimally-invasive surgery in term of

survival need to be validated on prospective series of patients

7. In patients with locally advanced tumours who underwent a

neoadjuvant treatment protocol, surgery gives the best results

in the subgroup of patients where a good response was

obtained (downsizing and lymph node sterilisation)

8. The benefice of surgery for patients with complete clinical

response to neoadjuvant treatment needs to be validated on

prospective studies

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List of scientific papers issued during PhD studies

Accepted/publishes papers in ISI journals:

1. B. Filip, I. Hutanu, I. Radu, M. G. Anitei, V. Scripcariu. “Assessment of

different prognostic scores for early postoperative outcomes after

esophagectomy” – accepted article Revista Chirurgia, impact factor 0.77

2. B. Filip, M. Scarpa, F. Cavallin, R. Alfieri, M. Cagol, C. Castoro.

Minimally invasive surgery for esophageal cancer: a review on sentinel

node concept –Surgical Endoscopy, DOI 10.1007/s00464-013-3314-8,

impact factor 3.42

Published papers in IDB or B+ journals: 1.Filip B, Hutanu I, Radu I, Anitei MG, Scripcariu V. Strategii terapeutice

în cancerul esofagian: rolul tratamentului chirurgical. Jurnalul de Chirurgie

(Iași) 2013; 9(1):137-148. DOI: 10.7438/1584-9341-9-2-4.

2.Filip B, Scripcariu V. Triplul abord in chirurgia cancerului esofagian,

Jurnalul de Chirurgie (Iași); 8(3): 237-243

3.Filip B, Huțanu I, Radu I, Scripcariu V. Robotic esophageal surgery: up-

to-date. Jurnalul de chirurgie (Iaşi). 2013; 9(3): 209-215. DOI:

10.7438/1584-9341-9-3-2.

4.Filip B, Huţanu I, Croitoru C, Aniţei MG, Radu I, Scripcariu V.

Transthoracic versus transhiatal esophagectomy: comparative study

regarding surgical approach in esophageal cancer. Jurnalul de chirurgie

(Iaşi). 2013; 9(4): 325-333. DOI: 10.7438/1584-9341-9-4-4.

International Congresses Oral presentation first author:

1.Filip B, Scarpa M, Cagol M, Alfieri R, Castoro C. Evaluation of

pronostic scores for postoperative morbidity after esophagectomy in

patients over 70 years. 23rd World Congress of the IASGO, București, 18-

21 iunie 2013

Oral presentations co-author:

1. Scarpa M, Scarpa Melania, Kotsafti A, Filip B, Cagol M, Alfieri R,

Bortolami M, Porzionato A, Constagliuolo I, Castoro C. Tumor

microenvironement in esophageal adenocarcinoma: innate and adaptive

immunity activation in neoplastic mucosa. 21st United European

Gastroenterology Week . Berlin , Germany , 12-16 Octombrie 2013

2.Scarpa M, Filip B, Cavallin F, Cagol M, Alfieri R, Castoro C.

Esophagectomy for esophageal cancer in elderly patients: clinical and

functional outcome. 21st United European Gastroenterology Week . Berlin

, Germany , 12-16 Octombrie 2013.

Posters first author:

1. Filip B, Scarpa M, Cagol M, Alfieri R., De Roit A., Castoro C., Ancona

E. Evaluation of the immediate inflamatory response and of the

performance status after Hybrid Minimally Invasive Esophagectomy- a

case control study, 21st International Congress of the European Association

of Endoscopic Surgery (EAES), Viena, Austria, 19-22 iunie 2013

2. Filip B, Scarpa M, Cavallin F, Cagol M, Alfieri R, Ancona E, Castoro C.

Predicting postoperative outcome after esophagectomy for cancer:

nutritional status is the missing ring in the current pronostic scores. 21st

United European Gastroenterology Week . Berlin , Germany , 12-16

Octombrie 2013.

3. Filip B, Scarpa M, Cavallin F, Alfieri R, Cagol M, Castoro C. Role of

sentinel node in esophagectomy for esophageal cancer: a systematic

review. 21st United European Gastroenterology Week . Berlin , Germany ,

12-16 Octombrie 2013

National Congresses

Oral presentations first author:

1.Filip B, M.G. Anitei, I. Hutanu, A. Gervescu, V. Scripcariu. Dezvoltarea

strategiilor multidisciplinare in tretamentul cancerului esofagian – rolul

suportului nutritional,tratamentul multumodal al dureriiin corelatie cu

extensia actului chirurgical/Multidisciplinay strategies in esophageal cancer

treatement- role of nutritional support,pain controle protocols, surgical

technique in correlation with surgical management. Congresul national de

chirurgie, Timisoara, 23-26 mai 2012

Posters first author:

1.Filip B, A. Gervescu, M. Gavrilescu, D. Scripcariu, V. Scripcariu

Morbiditatea postoperatorie in tratamentul cancerului esofagian in functie

de tehnica chirurgicala aleasa/Postoperative morbidity in the treatment of

esophageal cancer based on surgical approach. Congresul national de

chirurgie, Timisoara, 23-26 mai 2012

2.Filip B, V. Scripcariu Comparative study regarding surgical approach in

treatement of esophageal cancer. DocMedForum A doua sesiune de

comunicari Stiintifice pentru Doctoranzi, 30 november-2 december

2011, Cluj-Napoca