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DOI: 10.1177/0218492312449633
2012;20:443-449 Asian Cardiovasc Thorac Ann
McGuigan
Bassel Suffian Al-Alao, Haralabos Parissis, Igor J Rychlik, Alastair Graham and Jim
Prognostic factors in malignant pleural mesothelioma: role of talc pleurodesis
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Cardiovascular Surgery and affiliated journal of The Association of Thoracic and Cardiovascular
is the official journal of The Asian Society forThe Asian Cardiovascular & Thoracic Annals
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Original Article
Prognostic factors in malignant pleural
mesothelioma: role of talc pleurodesis
Bassel Suffian Al-Alao, Haralabos Parissis, Igor J Rychlik,
Alastair Graham and Jim McGuigan
Abstract
Objective: To examine baseline characteristics associated with survival in patients with malignant pleural mesothelioma.
Methods: 122 patients with histologically proven malignant pleural mesothelioma during the period 2000–2010 were
studied. Survival was evaluated by the Kaplan-Meier method with the logrank test. Cox regression analysis was used to
estimate the hazard ratios for possible prognostic factors.
Results: 105 (86%) patients had complete survival follow-up; 91 died and 14 (13.3%) were alive at the end of the obser-
vation period starting from the day of diagnosis. The median survival was 286 days (95% confidence interval: 212–359).
Talc pleurodesis was performed in 59 patients, and 17 had surgical interventions (2 chest wall resections, 2 extrapleural
pneumonectomies, and 13 decortications). Chemotherapy was used in 41 patients, port-site radiation in 68, and
combined therapy in 26. Cox regression analysis identified talc pleurodesis (p= 0.04), chemotherapy (p<0.001),
port-site radiation (p<0.001), and combined chemotherapy and port-site radiation (p<0.006) as favorable prognostic
factors after adjusting for age, sex, histologic subtype, smoking, and performance status.
Conclusions: Surgical intervention including decortications and extrapleural pneumonectomy had no effect on survival
in this series. Chemotherapy and radiation to port sites independently and in combination were associated with
improved overall survival in malignant pleural mesothelioma patients. Talc pleurodesis was an independent determinant
of survival, but further studies are warranted.
Keywords
Asbestos, mesothelioma, pleurodesis, survival, talc
Introduction
Malignant mesothelioma (MM) of the pleura is a rare
form of cancer that occurs in 5.3 males and 0.6 females
per 100,000 persons in Northern Ireland. It constitutes
0.1% of female and 0.9% of male malignancies. The
overall outcome is very poor with 1 - and 5-year sur-
vival of 27% and 8%, respectively.
1
Following asbestos
exposure, there is a latent period of up to 40 years;
therefore, given the wide use of asbestos until the
1980s, deaths from MM are expected to continue to
increase in Great Britain until 2015, at which point a
rapid decline should occur.
2
More specifically, the
annual number of mesothelioma deaths in the UK
was 153 in 1968, and it is predicted to reach 2450 per
year between 2011 and 2015.
2
Survival is poor at 10%
after 3 years, which is due in part to the symptoms of
MM presenting late when the disease is at an advanced
stage.
3
The difference between limited and locally
advanced disease is not always obvious; the staging
system for MM is not well embraced nor easily applic-
able in clinical practice. Moreover, studies on decorti-
cation or debulking and technically resectable tumors
have produced conflicting results and unsubstantiated
viewpoints. The current role of talc in MM is unknown.
A randomized phase III trial (MesoVATS trial) is cur-
rently recruiting to compare surgical pleurectomy and
talc pleurodesis, in order to determine which is better
at preventing fluid recurrence (ISRCTN: 34321019).
4
Asian Cardiovascular & Thoracic Annals
20(4) 443–449
ßThe Author(s) 2012
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DOI: 10.1177/0218492312449633
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Department of Cardiothoracic Surgery, Royal Victoria Hospital, Belfast,
UK
Corresponding author:
Bassel Suffian Al-Alao, MD, Department of Cardiothoracic Surgery, Royal
Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK.
Email: bassel@doctors.org.uk
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The objective of our study was to examine the role of
various therapeutic modalities in our practice, in con-
junction with baseline characteristics associated with
survival in patients with pleural MM.
Patients and methods
We retrospectively analyzed prospectively collected
data from a single institution. There were 122 patients
with histologically proven pleural MM during the
period 2000–2010. Their demographic data are given
in Table 1. Asbestos exposure due to occupation was
reported by 45 patients, 18 had incidental exposure,
and 22 reported no exposure. The European
Cooperative Oncology Group performance status was
0 in 18 (14.8%) patients, 1 in 41 (33.6%), 2 in 55
(45.1%), and 3 in 8 (6.6%).
Specimens were analyzed for malignant pleural
mesothelioma by an expert pathologist, and mesotheli-
oma was confirmed by immunohistochemistry when
indicated. The histologic subtypes are given in Table 1.
The treatment modalities are summarized in Table 1.
Talc pleurodesis was given to 59 patients, 41 received
chemotherapy, and 68 had radiotherapy. The radiation
was applied at the port site and thoracotomy site in 65
patients, the lungs in 2, and spinal metastasis in one;
21.3% of the patients underwent combined chemora-
diation. Pleurodesis was administered to patients who
had undergone diagnostic thoracoscopy and were
determined to be malignant by observation during the
process, and in those whose MM could not be ascer-
tained during diagnostic thoracoscopy by observation
but was diagnosed after the procedure (talc slurry via
chest tube was utilized).
Thoracoscopy was performed by thoracic surgeons
in accordance with a standard technique. An average of
4 g of sterile asbestos-free talc powder was administered
into the intrapleural space. After removal of the thor-
acoscope, a chest tube was inserted. The patients were
followed up every day, and the chest tube was removed
when the amount of fluid collected in the previous 24 h
was <100 mL. In patients who did not achieve reexpan-
sion 24 h after the procedure and had drainage of more
than 100 mL, suction was conducted at 20 cm H
2
O.
In patients who did not improve 72 h after suction, the
process was repeated with the same amount of talc
slurry administered in 100 mL of saline solution
through a chest tube at the bedside. The chest tube
was clamped for 2 h, and the patient was placed in
the prone, supine, and right and left decubitus positions
for periods of 30 min. The chest tube was removed
when the amount of fluid collected in the previous
24 h was <100 mL. No patient received systemic
corticosteroids or nonsteroidal antiinflammatory
drugs including pure analgesic medication during the
study. Chest radiographs were obtained immediately
after procedure, once daily, and after tube removal.
The majority of patients were subjected to talc treat-
ment once the diagnosis was established or even imme-
diately intraoperatively if the appearance was
suspicious enough and consistent with a clinical history
of pleural MM. The patients who did not receive talc
treatment were either not fit due to poor performance
status, or the surgeon anticipated that talc would
not work because the lung was trapped and not fully
or partially inflated. Clinicopathological variables
were explored (Table 1) and correlated with overall
mortality (Table 2).
All analyses were calculated using SPSS version 17.0
software (SPSS, Inc., Chicago, IL, USA). Univariate
analysis was used to compare data. Survival was calcu-
lated as median survival using the Kaplan-Meier
method. Comparisons of survival were carried out
using the logrank test to evaluate the equality of
Kaplan-Meier survival distributions. The Cox propor-
tional hazards regression model was used to identify
Table 1. Clinicopathological variables of 122 patients with
malignant pleural mesothelioma.
Variable No. of patients
Median age (years) [range] 68 [39–86]
Male sex 113 (92.6%)
Asbestos exposure
Occupational 45 (36.9%)
Incidental 18 (14.8%)
No exposure 22 (18.0%)
Smoking status
Smoker 72 (59.0%)
Ex-smoker 41 (33.6%)
Nonsmoker 20 (16.4%)
Histology
Epithelioid 97 (79.5%)
Sarcomatoid 15 (12.3%)
Mixed 8 (6.6%)
Desmoplastic 2 (1.6%)
ECOG performance status
0–1 59 (48.4%)
2–3 63 (51.6%)
Treatment
Talc pleurodesis 59 (48.3%)
Decortication 13 (10.7%)
Extrapleural pneumonectomy 2 (1.6%)
Chest wall resection 2 (1.6%)
No treatment 46 (37.7%)
Chemotherapy 41 (33.6%)
Port-site radiation 68 (55.7%)
ECOG: European Cooperative Oncology Group.
444 Asian Cardiovascular & Thoracic Annals 20(4)
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independent predictors of survival. A pvalue <0.05
was considered to be statistically significant.
Results
During the study period, 105 (86%) patients had com-
plete survival follow-up; 91 died and 14 (13.3%) were
alive at the end of the observation period starting from
the day of diagnosis. The overall 1-year survival rate was
41.8% and the 2-year survival was 13%. The median
overall survival time was 9 months with a 95%
confidence interval (95%CI) of 6.4–11.7 (Figure 1).
The median survival was weakly associated with sex
and older age (Figures 2 and 3). There was a trend
towards improved survival with epithelioid histologic
subtype (Figure 4). There was a survival benefit for
European Cooperative Oncology Group performance
status 0/1 vs. 2/3 (Figure 5). Moreover, there was a sur-
vival benefit favoring patients who underwent talc pleur-
odesis compared to those who had no treatment (median
survival, 12 vs. 6 months; p= 0.008), but there was no
difference when compared to other surgical interven-
tions (p= 0.77; Figure 6). Chemotherapy with or with-
out radiation was significantly associated with improved
Survival_Days
146010957303650
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Function
Figure 1. Overall survival curve for the 122 patients with
malignant pleural mesothelioma.
Table 2. Multivariate Cox regression analysis of independent
predictors of outcome in malignant pleural mesothelioma
patients.
Variable pvalue
Odds
ratio 95%CI
No treatment (reference) 0.078
Surgical management 0.731 1.151 0.516–2.567
Talc pleurodesis 0.041 0.618 0.390–0.981
Histology (epithelioid) 0.687 1.138 0.607–2.134
Age >69 vs. 468 years 0.135 1.423 0.896–2.262
Radiation (port-site) 0.001 0.300 0.149–0.604
Chemotherapy 0.000 0.123 0.042–0.362
Combined chemoradiation 0.006 0.202 0.065–0.627
ECOG performance
status 0/1 vs. 2/3
0.376 1.248 0.764–2.039
CI: confidence interval; ECOG: European Cooperative Oncology Group.
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
69+–censored
<= 68 –censored
69+
<= 68
Age (Binned)
p= 0.13
Figure 2. Survival function according to age group (median age,
68 years).
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
Male- censored
Female- censored
Male
Female
Gender
p=0.797
Figure 3. Survival function according to sex.
Al-Alao et al. 445
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outcomes, while only a trend towards significance was
noticed with port-site radiation alone (Figures 7–9).
Multivariate Cox regression analysis identified talc
pleurodesis, chemotherapy, port-site radiation, and the
combination of chemotherapy and port-site radiation
as favorable prognostic factors after adjusting for age,
sex, histologic subtype, smoking, and performance
status (Table 2).
Discussion
This study was a single-institution retrospective
survival analysis of patients with MM of the pleura,
over a 10-year period. Talc pleurodesis was the main
surgical palliation in these patients. There is no therapy
consensus in the literature and also a lack of data with a
high level of evidence to support any treatment modal-
ity over the best palliative care. Furthermore, MM of
the pleura exhibits a long latency period and there is a
tendency for the diagnosis to be obtained in the later
stages of the disease.
5
Metintas and colleagues
6
reported that during diagnosis, pleural masses are pre-
sent on computed tomography in 70% of patients, 58%
have moderate or large pleural effusions, and 28% have
lungs surrounded by tumor masses. Therefore, only a
small proportion of patients present in the early stages
and are free of comorbidities, enabling them to be
enrolled in trimodality treatment protocols.
A staging system for MM of the pleura was devel-
oped in the mid 1990s and was validated by Rusch and
colleagues.
7
Although advanced T and N status were
identified as poor prognostic factors, numerous subse-
quent publications have not reported or used TNM
staging. There are also drawbacks associated with sta-
ging: there is inaccuracy in describing the actual T stage
by the current imaging techniques, and there is no
accurate descriptor or stage when malignant pleural
effusion is present. Therefore, neither the Butchart
nor the IMIG TNM staging system are widely
implemented. In our series, imaging was based mainly
on chest radiography and computed tomography; med-
iastinoscopy was not carried out routinely. Positron-
emission tomography may correlate with the prognosis,
and it also depicts distal disease;
8
however, in our
series, positron-emission tomography was only used
in selected cases. Tumor staging has not been routinely
used in our patients, thus stratification according to
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
ECOG 2/3-censored
ECOG 0/1-censored
ECOG 2/3
ECOG 0/1
ECOG
p<0.001
Figure 4. Survival function according to performance status.
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
Epithelioid-censored
Non-epithelioid-
censored
Epithelioid
Non-epithelioid
Histology
p=0.315
Figure 5. Survival function according to histologic type.
Survival_Days
1400120010008006004002000
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
p=0.77
p=0.10
p=0.008
No Treatment-censored
Talc Pleurodesis-censored
Surgical Mangement-censored
No Treatment
Talc Pleurodesis
Surgical Mangement
Surgical Mangement
Overall p-value = 0.018
Figure 6. Survival function according to treatment modality.
446 Asian Cardiovascular & Thoracic Annals 20(4)
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TNM was not possible. The median survival in
this cohort of patients, despite the heterogeneity of
treatment, was between 6.3 and 11.6 months. This is
in line with other reports.
9
The main idea in the management of patients with
symptomatic pleural effusions caused by MM is to
achieve early and successful pleurodesis and prevent
the development of trapped lung. Video-assisted
thoracoscopy enables the procurement of diagnostic
biopsies and also assesses whether the lung is trapped.
In our practice, video-assisted thoracoscopic talc
pleurodesis is carried out in preference to the use of
bedside talc slurry. The overall survival of the video-
assisted thoracoscopic talc pleurodesis group appeared
to be better than in patients who only had direct pleural
biopsy, as well as in the limited number of patients who
received pleurectomy or decortication. The apparent
increased survival in these patients could be fortuitous
in this small series; it may relate to the process of
patient selection for the study or to the treatment
approach, or it may reflect the absence of harmful
modes of therapy. Talc has been reported to cause
apoptosis in mesothelioma cells in vitro;
10
however,
there is no evidence that the use of talc to treat MM
in humans does anything but facilitate pleurodesis.
It has been suggested that it can induce apoptosis in
tumor cells and inhibit angiogenesis, thus contributing
to better control of the malignant pleural effusion, but
both high tumor burden as well as defuse pleural
disease have been factors of poor talc compliance.
11
Other studies have identified increased pleural fluid
adenosine deaminase level in patients with malignant
pleural effusions as a potential predictor of talc pleur-
odesis outcome.
12
There is limited but emerging evidence that video-
assisted thoracoscopic debulking decortication can pro-
vide good symptom control, and may have a beneficial
effect on survival.
13
However, in our limited number of
patients, that was not the case: patients requiring decor-
tication to achieve reexpansion of the lung and pleur-
odesis may represent advanced-stage disease, with
chronically collapsed lung, hypoxia, shunting, and
reduced overall general health. The best treatment for
patients with MM of the pleura remains to be defined.
This is due to the heterogeneity of the patients at pres-
entation, the failure of various modalities to accurately
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
p<0.001
yes-censored
no-censored
yes
no
chemotherapy
Figure 7. Survival function according to chemotherapy
treatment.
Survival_Months
50403020100
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0
Survival Functions
p=0.09
yes-censored
no-censored
yes
no
port-side radiation
Figure 8. Survival function according to port-site radiation.
Cum Survival
Survival_Months
Survival Functions
Figure 9. Survival function according to combined
chemotherapy and port-site radiation.
Al-Alao et al. 447
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stage the disease, the relentless nature of this disease
which is usually well advanced at presentation, and
also the lack of randomized controlled trials in the
literature.
Although cure by surgery sounds inappropriate due
to the widespread nature of the disease, nevertheless,
procedures such as pleurectomy and decortication or
extrapleural pneumonectomy (EPP) aim to achieve
cytoreduction and facilitate maximal delivery of post-
operative radiotherapy. Chemotherapy has evolved in
the management of MM, and a randomized controlled
trial has shown the superiority of a combination regi-
men on median survival. Previous data also suggested
that the combination of cisplatin and pemetrexed posi-
tively influenced survival.
14
Whether prophylactic tract
irradiation is a wasted resource remains controversial.
15
In this series, tract irradiation appeared to be beneficial.
The value of radical surgery in potentially resectable
patients, by means of EPP, was shown to be superior
to pleurectomy and decortication or no resection in a
trial by the Lung Cancer Study Group.
16
Furthermore,
EPP followed by hemithorax radiation showed
improved survival in the early stage of MM and also
the best local control; however, for stages III and IV,
the median survival was 10 months.
17
A systematic lit-
erature review on the role of EPP in survival by Cao
and colleagues
18
concluded that there was a favorable
outcome in selected MM patients with radical surgery
as part of trimodality therapy. Similar outcomes where
reported by Flores and colleagues.
19
Nevertheless, EPP
is associated with variable morbidity and mortality,
and although it provides local control at least in
theory, it does not prevent the development of systemic
disease. Our own data were insufficient to derive any
conclusions. Prospective multicenter phase II trials of
radical multimodality therapy in early stage MM,
including induction chemotherapy and EPP, followed
by postoperative radiotherapy, have shown median sur-
vival of 17–20 months; the overall surgical mortality
was 7% and the overall morbidity was 50%.
Disadvantages included the prolonged overall treat-
ment time of 6 months and also questionable quality
of life, with high levels of psychological distress that
consumed much of the observed median improvement
of survival.
20–22
In our cohort study, the diagnosis of MM was con-
firmed using immunohistochemistry data of sufficient
quality in all patients. However, for prognostic factors,
some information on the study patients may be lacking
due to the retrospective nature of this analysis.
Therefore, the outcome may have been influenced by
the presence of unknown confounders. The inherent
selection bias may account for the apparent improved
survival in patients who were treated with talc pleurod-
esis. Hence survival benefits attributed to different
treatments must be interpreted with caution because
patients often receive various therapies in a variety of
combinations for different durations before and after
the diagnosis of MM was established. The small
number of surgical patients in our series showed no
advantage in survival compared to the talc pleurodesis
group. This report does not attempt to compare pallia-
tive talc pleurodesis with trimodality therapy including
EPP. Nevertheless, it provides an insight into the pal-
liative prognosis of a relentless disease; the main value
of these significant prognostic factors is to provide a
reference point for future prospective trials. Unlike stu-
dies reporting aggressive multimodality treatments, this
series represents a relatively heterogeneous group of
patients, mainly with advanced disease and pleural effu-
sions, undergoing cost-effective palliative management.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest statement
None declared.
Presented at the European Society of Thoracic Surgery
Meeting, Marseille, France, June 1–5, 2011.
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DOI: 10.1177/0218492312449633
2012;20:443-449 Asian Cardiovasc Thorac Ann
McGuigan
Bassel Suffian Al-Alao, Haralabos Parissis, Igor J Rychlik, Alastair Graham and Jim
Prognostic factors in malignant pleural mesothelioma: role of talc pleurodesis
This information is current as of August 9, 2012
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