Trial Information

Relationship Between Pleural Elastance and Effectiveness of Pleurodesis on Recurrent Malignant Pleural Effusion

1. PURPOSE To analyze the correlation between pleural elastance and the radiological
effectiveness (measured by chest tomography) of pleurodesis performed via catheters in
patients with RMPE. The secondary objectives of this study are: correlate pleural
elastance with quality of life, analysis of dyspnea and pain after the procedure,
clinical effectiveness, complications and mortality in 30 days.

2. METHODS Patients who participate in this study will be selected at the Pleural Diseases
Clinic of Department of Thoracic Surgery and Department of Pulmonology of the Medical
School of USP. Shall be deemed elected patients with: malignant pleural effusion
diagnosed by pleural fluid cytology and / or pleural biopsy; recurrent pleural effusion
(new accumulation of fluid after puncture) and symptoms (dyspnea and / or chest pain);
parcial lung expansion (> 50%) after puncture emptying confirmed by chest radiography;
Karnofsky index (KPS - Karnofsky Performance Status) > 30; and agreed to participate in
the study and sign an informed consent.

The investigators will include 140 patients in the study, predicting loss of some
patients.

3. PROCEDURE After insertion of the tube, this will be fixed to the skin with
nonabsorbable sutures and wound covered with a bandage. The catheter is connected to a
three-way stopcock. On its output side is connected to a delivery unit for measuring
central venous pressure or a gear connected to an electronic transducer of vascular
pressure. In the output is connected to the distal extension tube with the proximal end
of the valve and the distal end of Heimlich is connected to a collection bag. The
pleural pressure level will be zero at the time of the insertion site of the drain on
the skin. The pleural pressure is set to the value measured at end-expiration. The
pleural pressure is measured at baseline, after withdrawal of 10 ml of liquid and
thereafter every 400 ml of pleural effusion evacuated to the pressure to be negative,
from that moment the measurement will occur every 200 ml of pleural effusion drained to
obtain 800 ml of liquid. Patients that are removed less than 800 ml of liquid will be
excluded from the protocol. The pleural elastance is then calculated in cm H2O / L and
the data placed in a pressure curve by volume.

A chest radiograph is performed and the patient will be eligible for pleurodesis if
there is a lung expansion that will allow some contact between the pleural surfaces,
even partially.

The eligible patients for pleurodesis will be referred to an outpatient procedure room
or remain in their ward beds, where, under sterile conditions will be submitted to the
instillation of silver nitrate or talc mineral. Analgesia is given only when necessary.
The drain is kept closed for one hour, after this period, the drain is opened and the
patient discharged and instructed to return within 1 week in outpatient cases. A CT of
the chest will be held in the near-pleurodesis, while the patient is still on the drain
and with a maximum of five days after pleurodesis. In the outpatient possible
complications are evaluated. The drain is removed when less than 100 ml/day of pleural
fluid is drained.

After removal of the drain will be scheduled one month in return for clinical
evaluation and another CT scan of the chest. Since then the returns will be quarterly.
In all returns will be evaluated further chest radiographs, questionnaires of quality
of life, dyspnea and pain shall be applied and will be actively investigated the
occurrence of complications. Patients who fail to attend the consultation will be
contacted by phone. Non-scheduled queries occur in case of clinical necessity
(relapses, complications, etc.

Blinding The investigator will make measurements of pleural elastance not follow the
patients. Researchers who make assessments of patients and CT scans of the chest after
drainage and pleurodesis will be blinded to the measurements of pleural elastance.

4. OUTCOMES 4.1) RADIOLOGICAL EFFECTIVE In this study, the effectiveness will be measured
by radiographic tomography of the chest. Will be measured volumes of pleural fluid in
chest CT after placement of the drain and 1 month after pleurodesis.

The patient will be subjected to computed tomography of the chest without contrast. This
will be measured through the volume of pleural fluid. With use of axial slices, stipulate
every 2 cm segments. Will calculate the area occupied by the pleural effusion. Multiplying
the height of 2 cm will approximate the volume of this segment. Be inferred from the
approximate volume of pleural effusion by adding the volumes of all segments of 2 cm. The
unit of volume is milliliter.

The difference between volumes 1 month and near-pleurodesis indicate how much was the
re-accumulation of fluid in the pleural space, thus we provide a numerical value to be
related to the numerical value of pleural elastance. In case of recurrence within 30 days,
the TC will be held and that value will be considered post-pleurodesis.

4.2) CLINICAL EFFECTIVENESS In this study, the clinical effectiveness will be considered a
binary variable (success or failure). We will consider failure of pleurodesis when, at any
time of follow-up procedure was necessary some new procedure for emptying pleural effusion,
is puncture, drainage or thoracoscopy. Such procedures shall be appointed by the surgical
team of the Pleural Diseases Clinic of the HCFMUSP considering clinical criteria (symptoms:
dyspnea, cough and chest pain) and radiological (new fluid accumulation in chest
tomography).

4.3) ANALYSIS OF QUALITY OF LIFE To analyze the quality of life the investigators use the
WHOQoL-Bref. The WHOQOL-Bref is a reduced version of the questionnaire of quality of life
developed by the World Health Organization multi-cultural context, aiming to cover as many
countries and cultures as possible and thus can be used internationally, allowing the
comparison between the results obtained in different locations. This questionnaire has been
validated for the Portuguese language and covers the following areas: quality of life and
general health (scored by the patient), physical, psychological, social and environmental.
This questionnaire has been previously used for analysis of quality of life after
pleurodesis and will be applied by the same investigator during the initial evaluation, the
returns one month after the procedure and then quarterly.

4.4) ANALYSIS OF PAIN Pain assessment will be made by patient´s quantifying of the Visual
Analog Scale of Pain. The questionnaire will be applied by the same investigator during the
initial evaluation, the returns one month after the procedure and then quarterly.

4.5) ANALYSIS OF DYSPNEA The analysis of dyspnea will be made by quantifying the
functionality with the dyspnea scale of the British Medical Research Council (MRC). The
questionnaire will be applied by the same investigator during the initial evaluation, the
returns one month after the procedure and then quarterly.

4.6) SECURITY ANALYSIS For the analysis of safety procedures shall be deemed times of
hospitalization and drainage and occurrence of complications. Such data will be obtained
during the inpatient and outpatient follow-up as previously described. The expected
complications, and actively investigated, as the group's experience and literature are
fever, bleeding, infection (pulmonary and / or pleural), abdominal pain, prolonged drainage
(> 10 days), air leak, subcutaneous emphysema, respiratory failure, reexpansion edema and
death related to the procedure. Other complications will be recorded as the occurrence and
graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE).

5 - DATA COLLECTION Initial Assessment Will be collected the following data: age, sex,
primary tumor and number of puncture. All data will be included in a spreadsheet program
SPSS (Chicago, IL) and patients' names deleted after completion of collection. During the
initial assessment will also be filled in the questionnaires of quality of life WHO-Qol, MRC
dyspnea scale and Visual Analog Scale of Pain.

During the pleural drainage will be collected initial data from PP, the intermediate and
final and calculated elastance of the pleural space

Follow-up After chest tube removal patients will return in a month and then every three
months or as symptoms. In case of non-attendance, telephone contacts will be established
and, in case of death, the date will be noted for purposes of construction of the survival
curve.

In all returns the clinical data will be annotated seeking occurrence of any complications.
The quality of life questionnaires will be used again as soon as new chest X-rays are
performed. Examinations and additional consultations will be conducted according to clinical
need.

6) ANALYSIS OF OUTCOMES Radiation Effectiveness The difference between the pleural volume
after 30 days and peri-pleurodesis be correlated with measured pleural elastance. The
significance of this correlation is evaluated using the Pearson correlation coefficient.
Will be considered significant p <0.05.

Will be used to establish the linear regression equation that can predict the volume of
pleural fluid reacúmulo expected based on the measured pleural elastance.

Clinical Effectiveness The clinical effectiveness will be considered as a categorical value
and will be correlated with pleural elastance. The significance of this correlation will be
assessed by the Spearman test. Will be considered significant p <0.05.

Try Doc through a curve and the area under the curve values of elastance set from which
there is reduced clinical effectiveness.

Quality of Life The differences in scores on the questionnaire of quality of life in each of
its four areas after pleurodesis and before the same shall be correlated with pleural
elastance. The significance of these correlations will be assessed through the Pearson
correlation coefficient. Will be considered significant p <0.05.

Pain The difference in pain scores in the questionnaire after pleurodesis and before the
same shall be correlated with pleural elastance. The significance of this correlation is
evaluated using the Pearson correlation coefficient. Will be considered significant p <0.05.

Dyspnea Dyspnea is considered as categorical value and will be correlated with pleural
elastance. The significance of this correlation will be assessed by the Spearman test. Will
be considered significant p <0.05.

Complications Complications will be considered as categorical value (score ≥ 3 and ≤ 2 by
CTCAE) and will be correlated with the pleural elastance. The significance of these
correlations will be assessed through the Spearman test. Will be considered significant p
<0.05.

6.3) SURVIVAL A survival curve is constructed considering pleurodesis initial time and death
as the event. Censored are those which have not undergone the event until the end time of
the analysis. Cox regression will be held to the relevance of the following factors on
mortality: pleural elastance, KPS and primary neoplasm.

Methodology The measurement of partial elastance (first 800 ml) and not the total value can
change, since the pressure x volume curve is not always monophasic. The investigators will
measure the pressure until the end of the withdrawal of liquid and analyze the total
elastance, noting whether there will be significant changes.

Pleural pressure measurements and the water column pressure transducer vascular are
superimposable. Therefore, the investigators don't see problems in measuring pleural
pressure by different methods, depending on the non-availability of the transducer in all
clinics and wards of our hospital.