Trial Information

A Prospective, Randomized Controlled Trial for a Rapid Pleurodesis Protocol for the Management of Pleural Effusions

Malignant effusions are the 2nd commonest cause of exudative effusions and 75% are due to
lung, breast and lymphoma primaries. It is estimated that effusions take up about 20% of
pulmonologists' work. About 15% of lung cancers have effusions at presentation and 50% will
develop effusions during the course of the illness.

The current standard care of a symptomatic malignant effusion is to perform medical
thoracoscopy and talc poudrage pleurodesis to prevent recurrence. Reported pleurodesis
success with this technique is about 78%. However, this success rate is limited by the
presence of lung entrapment that prevents lung re-expansion and effective pleurodesis. Lung
entrapment occurs when there is a visceral pleural tumour peel encasing the lungs or when
endobronchial tumour causes lung/lobar collapse. Thoracoscopic pleurodesis also results in
significant hospital length of stay as chest tubes must stay in situ until the pleural space
is dry.

There is also established data on the use of outpatient tunnelled pleural catheters in
malignant effusions. Besides providing effective drainage in cases with entrapped lungs,
these catheters also result in spontaneous pleurodesis in 42 to 70% of cases. The attraction
of the catheters is that it enables early discharge of patients who already have a terminal
illness and an extremely poor prognosis (Prognosis is usually about 3-8 months depending on
the primary) However, the pleural catheters do not allow biopsies to be taken from the
pleura and the pleurodesis rate is both lower and slower than with talc poudrage.

This project hopes to capitalize on the strengths of both methods ie. talc poudrage via
thoracoscopy and indwelling pleural catheters, to increase the success of pleurodesis and to
decrease hospital stay. Indwelling catheters may improve the success data by draining
effusions associated with entrapped lungs that do not usually achieve pleurodesis with talc
poudrage alone. These catheters can be left in patients on a long term basis i.e. > 6
months. The attraction of the PleurxTM tunnelled catheter system is the low risk of
infections, air leaks (because of a one-way valve) and slippage.4-5 This type of study
involving combining both modalities has never been reported in the literature. There is no
such trial registered under clinicaltrials.gov. Pilot data (<20 patients) has been
previously presented at the American College of Chest Physicians Conference 2006 from
Harvard University with promising results.

Current data from our thoracoscopy service in SGH (Jan 2004 to June 2007), shows that our
pleurodesis success rate is 78.2%. However, complete success was achieved in 38.1%.7 This
data is in keeping with the reported literature and the failures/incomplete successes are
attributed to lung entrapment.3 Our data for hospital length of stay is 9.0 ± 4.0 (range 4
to 21) days.

We hypothesized that by combining thoracoscopic talc poudrage with tunnelled catheters, the
pleurodesis success rate could be improved by 15% to 93%, complete success to >75 % and
hospital length of stay approximately halved to 5 days or less. To test this hypothesis, we
want to conduct a prospective, randomized controlled trial comparing thoracoscopic talc
poudrage (standard care) to combined talc poudrage with tunnelled pleural catheters.

Procedure:

Patients who meet inclusion/exclusion criteria will be screened by investigators and trial
coordinators. After informed consent has been taken, patients will be randomized to either
of the study arms. Randomization will be done through a computer generated random list.
Baseline data and quality of life scores will be computed.

Patients will then undergo standard medical thoracoscopy in the endoscopy center including
the use of moderate sedation, prophylactic antibiotics for 1 week and 20F chest tube
insertion at the end of the procedure. The standard of 4-6 g of sterilized talc will be used
for talc poudrage.

In the combined procedure group, a PleurxTM tunnelled catheter will be inserted under
ultrasound guidance. As this procedure will be done concurrently with thoracoscopy, there is
no estimated increase in endoscopy time. If either group of patients is found to have no
gross evidence of malignancy at the time of thoracoscopy (ie. empyemas or tuberculous
pleurisy), then they will be withdrawn from the study and notified appropriately.

Patients in the standard therapy arm will emerge from the procedure with a chest tube while
the intervention arm will have both a chest tube and a tunnelled catheter. In the standard
therapy arm, the chest tube will be removed when there is no further air leak and when
drainage drops to ≤ 150 ml/day. After chest tube removal, the patient is fit for discharge.
In the intervention arm, the chest tube is removed when air leak stops. There will be no
need to wait for fluid drainage to decrease and theoretically, the patient can go home on
day 3 or 4 with the tunnelled pleural catheter.

Patients in the thoracoscopy only arm will be reviewed at 1 week in the outpatient clinic by
the investigators for suture removal and then again at 1 month for evaluation of
radiological success. This is the current standard practice. Quality of life assessment will
be also done at the one month visit by the trial coordinator. Subsequent follow-ups will be
with medical oncology as per standard practice including visits at about 3 months, 6 months
and 1 year.

Concurrent chemotherapy and radiotherapy will be allowed as per current standard of care.
Concurrent therapy is unlikely to impact our results because non-small cell lung cancers
which form the majority of our referrals have poor pleural effusion response to treatment.
This is the basis of why pleurodesis is the current standard of care. Chemosensitive tumours
like small cell lung cancers, ovarian cancers and lymphomas are seldom referred for symptom
management of pleural effusions unless they are refractory to chemotherapy. Again, these
patients will not be affected by concurrent 2nd/3rd line therapy. The small group of
patients who may be affected by simultaneous oncological management are those who have a
first time diagnosis of a chemosensitive tumour like small cell lung cancer or those with a
sensitive adenocarcinoma who are managed with Epidermal Growth Factor Tyrosine-kinase (EGRF)
inhibitors. These patients comprise <5% of our referrals and will have to analyzed
separately in subsets to determine their impact on our data. In our pilot review of SGH
thoracoscopy data, these cases formed a tiny proportion (1-2 cases) which prevented any
meaningful pilot study analysis.

The patients in the intervention combined treatment arm will be reviewed at outpatient
clinic either the next day or within 48 hours. They will undergo drainage via the tunnelled
catheter. If drainage is less than 150 ml, the PleurxTM catheter will be removed. Otherwise,
the patient will be recalled over the next 24-48 hours till such drainage is achieved. If
drainage persists for greater than 5 visits, then these patients will be deemed to have an
entrapped lung and will need long term pleural catheterization. Subsequent management will
be billed to the patient as part of their usual care. In the rare occurrence of a blocked
pleural catheter, a fibrinolytic flush (using streptokinase or alteplase) will be used. This
will be done using established protocols for management of blocked catheters.

The primary end points will be pleurodesis/pleural catheter success. Complete success is
defined in the literature to be no or minimal re-accumulation of pleural fluid at 30 days.
Partial success is defined as partial (≤ 50%) re-accumulation of fluid with some resolution
of symptoms and the absence of any further therapeutic interventions at 30 days. If any of
these conditions are not met then the procedure is deemed to be a failure.

Secondary endpoints are

1. Hospital length of stay. This will be determined primarily by the primary attending
physician based on the patient's medical condition. Patients will be considered
'pleurodesis fit for discharge' the day the chest tube is removed. The chest tube will
be removed in the absence of pleural space infection or air-leak (i.e. complications)
if the effusion drainage drops to ≤ 150 ml/day and if there is lung re-expansion.

2. Complication rates for infections, bleeding, air-leaks/pneumothorax, tumor seeding of
the track

3. Pain scores

4. Analgesia/sedation requirements

5. Talc dose required

6. Quality of life analysis using St George's respiratory questionnaire (pre and post),
Borg's scale, ECOG and Karnofsky score.

7. Re-admission and repeat procedure rates for complications related to pleurodesis or
re-accumulation of fluid. We aim to track the patients for 1 year.