Preoperative selection and conditioning of patients with esophageal cancer

Treatment of esophageal cancer
Esophageal cancer is a highly lethal disease with an overall 5-year survival
rate of approximately 20% (1). The incidence in the Netherlands (1800 pts) is
increasing rapidly in the last three decades, especially due to chronic reflux
esophagitis in patients with obesity and Barrett related reflux disease. An
increased incidence is also observed in the elderly population with a peak
shifting towards the 65-70 years. Currently, promising treatment methods, such
as neo-adjuvant chemo-radiation and tyrosine kinase inhibitors, are emerging
with frequently reported complete responses (25-30%). Nevertheless, surgery
remains the primary curative option.

Disadvantages of treatment
However, esophagectomy as a high-risk complex surgical procedure has severe
postoperative complications of around 35-50% and a relatively high rate of
postoperative mortality between 3% and 15%. The most common complications are
respiratory (40%-50%) ranging from atelectasis / pneumonia to respiratory
failure (ARDS and acute lung injury) often accompanied by sepsis. Besides
respiratory complications, cardiac complications are also common with a
frequency of 15-20%, mostly due to cardiac arrhythmias (2).

Risk analysis
Preoperative risk stratification for postoperative mortality and morbidity may
help patients and families address the magnitude of both the disease and the
therapy. It is pivotal for both the patient and the surgeon to realistically
assess the magnitude of the surgical insult. So far a reliable individual risk
analysis stratification to guide surgeons and oncologists in the
decision-making is missing and it should be done in the context of an overall
clinical judgment. Until now, selection is based on patient*s characteristics,
comorbidity index, including mental and physical condition, and tumor staging
with CT/EUS and PET/CT.
With a more appropriate risk-prediction, which would be partly based on the
immunological status of the patient, we might be able to identify patients with
high estimated morbidity and mortality. A careful selection based on a more
advanced immunological status may be helpful in the implementation of an
individual treatment strategy and to perform adequate preoperative
interventions to reduce postoperative complications.



Immunological response
The surgical trauma during esophagectomy and necessity of one lung ventilation,
using double lumen endotracheal intubation, cause early activation of
leucocytes, macrophages and endothelial cells with enhances expression and
release of anti- and pro-inflammatory cytokines (TNF-α, CRP, FABP*s,
procalcitonine, IL-1, IL -2, IL-6, IL-8, IL-10) and chemokine receptors
(CXCR1/CXCR2). The acute phase response, consisting of an initial release of
TNF-α, IL-1 and IL-6 the so-called primary mediators of acute stress, occurs
within 30-60 minutes with a sharp increase after 2-4 hours and a maximum of
24/48 hours after the surgical trauma. A local response of IL-1 stimulates the
synthesis and release of IL-2 by CD4+ T-helper lymphocytes, the cell mediated
immunity, leading to an overall systemic effect. Interleukin 10 is the most
important anti-inflammatory cytokine and inhibits pro-inflammatory cytokine
secretion of IL-1, IL-6 and TNF-α from monocytes, macrophages and Th1
(T-helper) cells. Furthermore, the Fatty Acid Binding Proteins (FABPs) plays an
important role in activating the immune system by TNF and insulin and may be
used as a potential serum marker for systemic inflammatory response syndrome
(SIRS).

Significance of elevated cytokine concentrations
Patients with an elevated concentration of cytokines have an increased risk of
renal failure, myocardial and respiratory dysfunction (14, 22, 23). In
addition, there appears to be a positive correlation between IL-6 and the
impact of the surgical procedure (operating time, blood loss, amount of fluid
administered) (11). So, the levels of primary cytokines could be used as a
prognostic marker in relation to the development of early and serious
complications. Moreover, they also may have a potential negative correlation
with the one-and 5-year survival in these patients. (12)
Factors affecting the immune response
Surgery generally has a negative impact on the immunological status of
surgically explored patients. However, patients diagnosed with esophageal
cancer have a severe increased risk of impaired immunological response. The
cause of an impaired immunologic response is different and several patients*
characteristics could be responsible for a decreased immunological reaction.
For example: advanced age (>70 years), a high comorbidity risk profile, the use
of neo-adjuvant chemo-radiation and anesthetic factors including the method and
duration of intubation (one-lung ventilation). Research is needed to determine
the significance of these characteristics in the immunological status of the
individual patient. Reducing the systemic stress response could be an important
contribution to avoid morbidity and mortality, but may also affect long-term
survival as was reported in some studies. (3-10,12)

Additional to the above systemic effects several other factors are to consider
affecting the immunological response. Differences in response may also be
related to:

1. Cytokine genotyping of the patient.
SIRS, which occurs in each patient after an esophagectomy, is accompanied with
an elevated TNF-α production by monocytes increased level of FABPs and
expression of IL-6. FABPs maintain membrane integrity by protecting the cell
from the detergent effects of excess non-protein bound fatty acids. They
facilitate the transport of fatty acids and other lipid mediators throughout
the cell and as a potential central regulator of common pathways controlling
inflammatory and regulating metabolic signaling. Polymorphism of TNF-α gene
locus in particular 308 (TNF-α genotype 308), which is also observed in other
critically ill patients, is associated with an increased mortality and poor
prognosis and can be analyzed in our surgical laboratory (21). Therefore,
screening of this high-risk group seems to be appropriate.
2. Prolonged intubations and re-intubations also induce SIRS and are
associated with postoperative respiratory morbidity. Patients participating in
a preoperative respiratory physiotherapy program (Intensive Muscular Training
(IMT), will develop a greater vital lung capacity by increasing their skeletal
muscle mass. The effect of this intervention may be observed in our study as
well.

Intervention
3. Oxygenation
During esophagectomy, the surgeon explores the esophagus usually with a right
sided thoracotomy in case of a mid esophageal tumor or trough a left sided
approach in the case of a distal tumor. Both procedures require one-lung
ventilation (OLV) for an optimal approach. Routinely, a double lumen tube is
used for that purpose, with pressure controlled ventilation on the ventilated
lung. Pressure controlled ventilation with low tidal volumes (and higher PEEP
values) lead to a reduction of mortality in patients with ARDS (13). The
benefit of this strategy seems to be a reduction of the sheer stress of the
alveoli, thereby attenuating the inflammatory responses associated with
mechanical ventilation.
Nevertheless, even with the use of lung protective ventilation (i.e. low tidal
volumes) during esophageal resection, there is still a high respiratory
morbidity up to 49%. While some of this morbidity is related to a
ventilator-induced injury of the continuously ventilated lung, respiratory
morbidity may also be the consequences of the lung collapse on the surgical
side for a relatively long period. Besides, there is growing evidence that an
early inflammatory response might represent the final pathway that heralds the
onset of respiratory complications. (14)

High Frequency Jet Ventilation
A potential method of avoiding and attenuating some of the associated
complications with OLV may be obtained by the use of High Frequency Jet
Ventilation (HFJV) on both lungs (15-16). It provides adequate oxygenation with
only small tidal volumes, thereby reducing sheer stress on the non-exposed lung
and preventing complete collapse of the exposed lung. The surgeon should be
able to retract the exposed lung sufficiently to enable a good surgical view of
the esophagus without causing collapse and atelectasis of the lung. HFJV is
characterized by high frequency (>100/min) ventilatory cycles and very low
tidal volumes.

Literature
In a recent published article, Buise et al (17) concluded that HFJV for both
lungs, using a single-lumen tube, is a safe and adequate ventilation technique
during esophagectomy. HFJV had no significant influence on the incidence of
postoperative pulmonary complications, but reduced the perioperative blood loss
and led to a lower need for fluid replacement. However, Buise et al failed to
test HFJV compared to the immunological status of the patient and especially
the cytokines concentrations during surgery. In a randomized trial of Misiolek
et al (18) in which 29 patients receiving HFJV and 31 patients receiving
one-lung ventilation, they concluded that HFJV is a safe and comparable option
of ventilation for open-chest thoracic procedures. Ender et al (19) concluded
that HFJV could be safely used during minimal invasive coronary bypass graft
surgery with a reduction in the peak inspiratory pressure (from 32.1 ± 5.9 to
10.0 ± 2.8 mbar), but at a cost of a rise in PaCO2. Finally, Moloney et al (20)
described in a review article none significant differences in complication
rates between conventional ventilation and HFJV. There appears to exist a
safely use of HFJV in respect to oxygenation. These authors do speculate
however over a study design whereby these two types of ventilation should be
compared in relation to cytokine concentrations. Based on these results and our
own experience in the UMCG, the anesthetic department considers the use of HFJV
as a safe method, which can be used as a proven method in thoracic surgery.

Primary Objectives:
This study consist of:
1) a prospective cohort study in which all patients with esophageal cancer,
selected for esophagectomy, and willing to be included in this cohort, are
followed to assess their complications, short en long term outcome in relation
to their immune response.
2) a pilot randomized clinical trial that is performed within this cohort
including all patients with an ASA <=2, that are willing to participate.

The aim of the prospective cohort study is to analyze the impact of
immunological response during treatment of patients with esophageal cancer who
are selected for esophagectomy on complications, short and long-term outcome in
the context of patients* and tumour characteristics. Preoperative risk
stratification for postoperative mortality and morbidity may help patients and
families address the magnitude of both the disease and the therapy.

The aim of the pilot randomized clinical trial (pilot RCT) is to explore
whether High Frequency Jet Ventilation (HFJV), as a strategy to decrease the
anesthesiological stress by improving oxygenation compared to the standard
double lumen technique, can reduce the inflammatory stress response during
esophagectomy.

Secondary Objectives:
Prospective cohort study
- To explore the value of polymorphism at TNF-α gene locus (TNF-α genotype 308)
as a useful predictor of preoperative risk assessment for mortality and
morbidity after esophagectomy.
- To investigate the added value of the immunological response as a predictor
for mortality and morbidity in combination with known risk models, such as the
ASA-classification and the POSSUM.

Pilot RCT
- To investigate whether there is a relation between both breathing techniques
(conventional vs HFJV) and the conduct of the operation (blood loss, operation
time), (severity of) complications (especially pulmonary) and in hospital
and/or 90 day mortality.
- To investigate differences between HFJV and conventional ventilation with
recorded intraoperative anesthesiologic variables: BIS (bispectral edge),
cardiac output measurements (using PICCO (Puls Contour Cardiac Output)),
transcutaneous CO2 (TcCO2) measurement, ROS, EVLW (extra-vascular lung water)
and ITBV (intrathoracic blood volume.

Prospective cohort study
Blood samples (10ml) will obtained via venapunction during the entire hospital
admission at various predetermined moments (see overview for details).
Immediately after extraction, blood samples will be centrifuged at 14.000 rpm
for 10 minutes. Sera and plasma will be separated and samples will be stored in
aliquots at -70 degrees. Cytokine levels will be measured using specific
enzyme-linked immunosorbent assays (ELISAs). For all tests commercially ELISA's
en Western Blots are available. The following concentrations will be measured
by an ELISA analysis: TNF-α, CRP, FABP, procalcitonine, IL-1, IL-2, IL-6, IL-8,
IL-10 and chemokine receptors (CXCR1/CXCR2) and the real time PCR genotyping
will be determined.

Overview of blood sampling:


• 1e blood sample: prior for the start of neo-adjuvant treatment
• 2e blood sample: day 7 of neo-adjuvant treatment therapy
• 3e blood sample: prior for the start of participation of IMT study
• 4e blood sample: prior to the start of operation
• 5e blood sample: during two lung ventilation
• 6e blood sample: during one lung ventilation
• 7e blood sample: end of surgery
• 8e blood sample: first day at ICU (12-24 hours after end of surgery)
• 9e blood sample: second day at ICU (between 24 and 48 hours after surgery)
• 10e blood sample: between 48 and 72 hours after the arrival on the oncology
department
• 11e blood sample: between 48 and 72 hours after the last blood sample

Note: The period of neoadjuvant treatment is 5 weeks, followed by a rest period
of 5-6 weeks before surgery is performed. The average treatment is 14 weeks,
while the average ICU stay is 2 days and 2 weeks on the surgical department.

Pilot RCT: HFJV
Patients who agree to participate in the prospective cohort study will be asked
to participate in the intervention study as well (provided an ASA <= 2).
Patients who decide to participate will be randomized to receive either
traditional ventilation or HFJV. Randomization will be performed by the Trial
Coordination Center (TCC) of the UMCG.

Oxygenation
Conventional ventilation will consist of 6-8 ml/kg/breath, at approximately 12
breaths/min to achieve an end tidal CO2 of 4.0-5.0 kPa. Intubation will be
occurred with an appropriately sized double lumen tube (female 37/39, male
39/41) for OLV and its position will be confirmed with a bronchoscope. HFJV
will be based on PaCO2 during tumor resection. A standard single lumen tube
will be inserted. These patients will receive HFJV of both lungs. During
surgery all measurements are continuously recorded by the RUGLOOP II data
logging system.

Blood samples will be taken during surgery on predetermined moments (see
overview), at the start of operation, during two-lung ventilation, during
one-lung ventilation (or during HFJV) and at the end of operation. Blood
samples will be stored in aliquots at -70 degrees.
Concentrations of TNF-α, CRP, FABP, procalcitonine, IL-1, IL-2, IL-6, IL-8,
IL-10 and chemokine receptors (CXCR1/CXCR2) will be determined by an ELISA.

Prospective cohort study
As hematological testing is performed on a frequent basis anyway in patients
with esophageal cancer burden and risks are neglect able. Frequent vena
punction carries limited risks and is usually well tolerated.


Pilot RCT
We expect a decreased inflammatory response in patients who are randomized in
the HFJV group, which could be a benefit for an individual patient.
Based on data from literature and our own experience in the UMCG, the
anesthetic department considers the use of HFJV as a safe method, which can be
used as a proven method in thoracic surgery. Unforeseen complications or
difficulties with the use of HFJV during esophagectomy will come clear during
this pilot study.