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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