Pleurodesis in malignant pleural effusions: a randomized
study of tetracycline versus bleomycin
E. Martínez-Moragón*, J. Aparicio**, M.C. Rogado*, J. Sanchis*,
Pleurodesis in malignant pleural effusions: a randomized study of tetracycline
bleomycin. E. Martínez-Moragón, J. Aparicio, M.C. Rogado, J. Sanchis, F. Sanchis, V.
Gil-Suay. ERS Journals Ltd 1997.
ABSTRACT: Malignant pleural effusions are commonly managed with tube tho-
racostomy drainage followed by chemical pleurodesis. Both tetracycline and bleomycin
have been shown to be effective for intrapleural instillation, although neither agent
has definitively proved advantages over the other. The aim of the present study was
to compare these two agents in terms of response rate and toxicity profile.
A prospective, randomized trial was carried out in a single centre. Between May
1993 and January 1996, 62 evaluable patients with proved malignant pleural effu-
sion were allocated to receive either intrapleural tetracycline (1.5 g) or bleomycin
(60 mg) after the same drainage procedure. Demographic, clinical and fluid para-
meter data were comparable in both groups. Response was evaluated at 1, 3 and 6
months after pleurodesis.
Mean survival and time to relapse did not differ between the two groups. No sta-
tistically significant differences were found in terms of efficacy at each evaluation
time. Overall, 16 (52%) and 20 (64%) patients had a recurrence of pleural effu-
sion during follow-up in the tetracycline and bleomycin arms, respectively. Fever
was most common in bleomycin-treated patients (p=0.024) while pain was most fre-
quent in the tetracycline arm (nonsignificant).
Since no study agent was superior to the other in this trial, we suggest that eco-
nomic costs, drug availability and medical skill should be considered in the choice
of a sclerosing agent.
Eur Respir J 1997; 10: 2380–2383.
Malignant pleural effusions are a common medical
mg) for the treatment of malignant pleural effusions.
problem in patients with cancer. The usual treatment of
The same investigators performed all procedures in a
these recurrent, symptomatic effusions is intrapleural
single institution. Approval was granted for the study
instillation of a chemical substance in an attempt to pro-
by the Ethics Committee of the hospital.
duce pleurodesis. Several agents have been employedfor this purpose. However, there have been very few
controlled trials to ascertain which one is superior in
Patients eligible for the study were those with malig-
nant pleural effusion causing respiratory symptoms, proved
Tetracycline, talc and bleomycin are considered the
by cytological examination or pleural biopsy, and an ex-
primary sclerosing agents . Talc appears to be the most
pected survival of at least 1 month with a Karnofsky score
effective and least expensive; however, it is more diffi-
of 50 or more. Although previous drainage procedures
cult to employ, frequently requiring pleuroscopy or even
were not considered as grounds for exclusion, no prior
thoracostomy for instillation . Therefore, tube thora-
intrapleural instillation therapy was allowed. Patients who
costomy drainage followed by application of tetracy-
had had chest radiotherapy during the preceding 2 weeks,
cline or bleomycin is the commonest method of chemical
and those who had previously received systemic bleomy-
pleurodesis. Although the response rates to tetracycline
cin, were also excluded. No changes in systemic chemo-
and bleomycin seem comparable , there have been
therapy or hormonotherapy were permitted in the 4 weeks
few randomized comparative trials [4–6]. The purpose
prior to study, although new therapies could be initiated
of the present study was to determine, within a single
after pleurodesis. Patients in whom complete lung expan-
institution, whether any differences exist between these
sion was not possible, due to either obstructive atelect-
sclerosing agents in terms of efficacy or side-effects.
asis or loculate effusion, were considered ineligible. All
Materials and methods
patients denied allergies to the study drugs.
A prospective, randomized study was planned to com-
After giving informed consent, patients were randomly
pare intrapleural tetracycline (1.5 g) and bleomycin (60
assigned by computer to one of two groups. The protocol
T E R A C Y C L I N E V E R S U S B L E O M Y C I N I N P L E U R A L E F F U S I O N S
used was tube thoracostomy suction drainage until re-
Table 1. – Characteristics of patients in both treatment
expansion of the lung, and the amount of fluid drained
was less than 100 mL·day-1. Tetracycline (1.5 g dilut-
ed in 100 mL normal saline solution plus 9 mL 5% lig-
nocaine) was then instilled intrapleurally in the firstgroup of patients. Similarly, bleomycin (60 mg diluted
in 100 mL normal saline solution) was instilled in the
second group of patients. Following this, the tube was
clamped for 4 h, but the patient's position was not rot-
ated. Finally, the tube was unclamped and suction drain-
age was resumed until the fluid obtained was less than
100–150 mL·day-1. At this time, the chest tube was re-
moved. Adverse effects of the procedure were system-
Before pleurodesis, the size of the pleural effusion in
a posteroanterior chest radiograph was catalogued as
"moderate", when extending from the diaphragm to the
pulmonary hilum, and "massive", when exceeding the
hilar region. Patients were followed up with chest radio-
graphs at 1, 3 and 6 months after pleurodesis. Responses
were classified as: 1) complete (no clinical or radio-
logical recurrence of pleural effusion); 2) partial (small
amount of fluid reaccumulation in the chest radiograph,
but no symptoms); and 3) failure (reaccumulation of fluid
Values are expressed as absolute number of patients, and per-
causing symptoms or needing thoracocentesis) [7, 8].
centage in parenthesis, unless otherwise noted. *: mean±SD(range); +: median (range).
therapy and 32–35% underwent surgery for their primarytumour. Time since the diagnosis of cancer to the onset
Both study groups were compared with respect to
of pleural effusion was 28±36 months for the tetracy-
demographic features, performance status, site of pri-
cline-treated group versus
22±42 months for the bleomy-
mary tumour, number of metastases and disease char-
cin-treated group. There were no significant differences
acteristics. The t-test was used for continuous variables
between the two groups with regard to demographic char-
and the Chi-squared or Fisher's exact tests, when appro-
acteristics, primary disease or prior treatment. Clinical
priate, for comparison of proportions. Response rates
and radiographic features are shown in table 2, and pleu-
between the two agents were compared at each evalu-
ral fluid parameters in table 3. Again, these figures were
ation (1, 3 and 6 months) using the Chi-squared test.
Time to recurrence and survival were analysed using
The mean volume of pleural fluid drained before pleu-
the Kaplan-Meier method , and curves were com-
rodesis was significantly greater in the bleomycin-treated
pared with the Mantel-Haenszel test . All statisticalcomparisons between bleomycin and tetracycline were
Table 2. – Presenting symptoms and radiographic fea-
two-sided and carried out at the 0.05 significance level.
Between May 1993 and January 1996, 70 consecu-
tive patients entered the study. Thirty five patients were
randomly assigned to the tetracycline-treated group and
35 to the bleomycin-treated group. Eight patients (11%)
were ineligible due to rapid progression of systemic dis-
ease and death (five) or lack of follow-up (three). Thus,
62 patients were eligible for analysis (31 included in
the tetracycline-treated group and 31 in the bleomycin-
Demographic and primary disease characteristics are
summarized in table 1. The majority of patients had lung
or breast cancer, with one other site of metastases, alongwith pleural malignancy, and a good initial performance
Values are presented as number of patients, and percentage
status. Nearly half had received prior systemic chemo-
Table 3. – Pleural fluid parameters before pleurodesis
*: All other cases were diagnosed through pleural biopsy. Dataare expressed as number of patients (percentage) or as mean±SD.
LDH: lactate dehydrogenase.
group, as was mean duration of chest drainage afterpleurodesis in the tetracycline-treated group (table 4).
However, these differences were not clinically relevant.
There were no complications of tube thoracostomy. Ad-
verse experiences were reported in 15 (48%) bleomycin-
Fig. 1. – Actuarial curves showing the realpse time of pleural effu-
treated patients and 17 (55%) tetracycline-treated patients.
sion after pleurodesis. There was no significant difference between
Pain was usually self-limiting and, depending upon the
treatments. : bleomycin; : tetracycline.
severity, managed with paracetamol or opiates. Therewere no significant differences in the incidence of side-
effects between the treatment groups, except for feveroccurring more frequently in the bleomycin group (table
Table 4. – Procedure-related aspects and side-effects
4). Fever reached 38–39°C and lasted for 1 day. Antipyret-ics were not administered routinely, and no post-treatment
infections were identified. No severe or life-threateningadverse experiences were noted in this study.
Table 5 shows the response rate to both agents at each
evaluation point. The percentage of failures did not dif-
fer between the two groups. A trend for a higher com-
plete response rate was noted in the tetracycline arm.
Nevertheless, it was not statistically significant at 1, 3
Overall, 16 and 20 patients had a recurrence of pleural
effusion during follow-up in the tetracycline and bleo-
mycin arms, respectively. The recurrences included two
of the 10 (20%) partial responses that became failures in
the tetracycline group, and four of the 13 (31%) in the
bleomycin group. Mean time to relapse was 32±16 days
for tetracycline and 36+41 days for bleomycin, with over-lapping actuarial curves (fig. 1). Sixteen patients died
+: p=0.017; #: p=0.019; †: p=0.024, versus
in each arm, with a mean follow-up time of 7 months.
ed group. Data are expressed as number of patients (percent-
Median survival was 13 months in the tetracycline arm
and 9 months in the bleomycin arm (nonsignificant; fig.
Table 5. – Response to chemical pleurodesis
*: for comparison of CR with PR and Failure combined. NE:
not evaluable (chest radiography not performed, patient lost
Fig. 2. – Probability of survival for all patients in both arms. There
to follow-up, or death); CR: complete response; PR: partial
was no significant difference between treatments. : bleomycin;
T E R A C Y C L I N E V E R S U S B L E O M Y C I N I N P L E U R A L E F F U S I O N S
times greater than those of tetracycline at the doses usedin this study. If tetracycline is selected, we recommend
The prognosis of patients with malignant pleural effus-
ion is poor, although it varies depending on the histolog-ical features of the primary tumour. Chemical pleurodesisis a palliative treatment intended to obliterate the pleural
space. In the last two decades, tetracycline has becomethe sclerosing agent of choice because of its safety, in-
Reid PT, Rudd RM. Management of malignant pleural
expensiveness and consistent efficacy [11–13]. Although
1993; 48: 779–780.
it has been less extensively studied, intrapleural bleo-
Moffett MJ, Ruckdeschel JC. Bleomycin and tetracy-
mycin is an alternative agent for pleurodesis. Bleomycin
cline in malignant pleural effusions: a review. Semin
seems to cause less pain during instillation, but is more
expensive than tetracycline. Data on effectiveness are
Walker-Renard PB, Vaughan LM, Shan SA. Chemical
pleurodesis for malignant pleural effusions. Ann Intern
There are only three randomized trials comparing these
Gupta N, Opfell RW, Padova J, Margileth D, Souadjian
two agents in the literature. Two of them showed no sig-
J. Intrapleural bleomycin versus
tetracycline for control
nificant differences in response rates, although the num-
of malignant pleural effusion: a randomized study. Proc
ber of patients was small [4, 5]. In a recent, multicentre
Am Assoc Cancer Res
1980; 21: 366.
study, bleomycin was more effective at both 30 and 90
Kessinger A, Wigton RS. Intracavitary bleomycin and
day evaluations . Toxicity was similar between groups
tetracycline in the management of malignant pleural effu-
in all these trials. Unfortunately, drug doses differed
sions: a randomized study. J Surg Oncol
1987; 36: 81–83.
among studies (0.5–1 g for tetracycline; 60–89 mg for
Ruckdeschel JC, Moores D, Lee JY, et al
therapy for malignant pleural effusions: a randomized
In the present study, both agents seem equivalent in
comparison of bleomycin and tetracycline. Chest
terms of efficacy. A trend for a higher complete response
rate in the tetracycline arm might be related to the higher
Sanchez-Armengol A, Rodriguez-Panadero F. Survival
doses used (1.5 g), as suggested by its mechanism of
and talc pleurodesis in metastatic pleural carcinoma,
action. In an experimental model, intrapleural tetracycl-
revisited. Report of 125 cases. Chest
1993; 104: 1482–1485.
ine acts in a dose-dependent way, stimulating mesothelial
Paladine W, Cunningham TJ, Sponzo R, Donavan M,
cells to release a growth-factor-like activity for fibro-
Olson K, Horton J. Intracavitary bleomycin in the man-
blasts that induces pleural fibrosis [16, 17]. By contrast,
agement of malignant effusions. Cancer
1976; 38: 1903–
the injection of bleomycin was ineffective in creating
pleural fibrosis in rabbits with normal pleura, thus sug-
Kaplan EL, Meier P. Nonparametric estimation from
gesting a possible antineoplastic effect . G
incomplete observation. J Am Stat Assoc
1958; 53: 457–481.
.  proposed that the use of larger doses of tetra-
Mantel N. Evaluation of survival data and two new rankorder statistics arising in its consideration. Cancer
cycline (≥1 g) may increase the probability of success-
1966; 50: 163–170.
ful pleurodesis. In a previous retrospective study, the
Zalonik AJ, Oswald SG, Langin M. Intrapleural tetra-
authors showed that tetracycline doses of 1.5 g were more
cycline in malignant pleural effusions. A randomized
effective than 1 g (although differences were not statist-
1983; 51: 752–755.
ically significant) without increasing toxicity . There-
Gravelyn TR, Michelson MK, Gross BH, Sitrin RG. Tet-
fore, we selected the first dosage for the present trial.
racycline pleurodesis for malignant pleural effusions. A
Pain is the most commonly reported side-effect dur-
10 years retrospective study. Cancer
1987; 59: 1973–1977.
ing the instillation of tetracycline, and in the following
Sherman S, Grady KJ, Seidman JC. Clinical experience
days. In the present and other studies [5, 6], the incidence
with tetracycline pleurodesis of malignant pleural effu-
of pain was not significantly different between both
sions. South Med J
1987; 80: 716–719.
groups, probably due to the systematic inclusion of a
Bitran JD, Brown C, Desser RK, Nozloff MF, Shapiro
local anaesthetic within the tetracycline preparation. Fever
C, Billings AA. Intracavitary bleomycin for the control
was most frequent among bleomycin-treated patients, as
of malignant effusions. J Surg Oncol
1981; 16: 273–277.
reported in previous , but not in all , randomized
15. Ostrowski MJ. An assessment of the long-term results
studies. Serious complications were not seen in our trial.
of controlling the reaccumulation of malignant effusions
Overall, toxicity of pleurodesis with both agents was
using intracavitary bleomycin. Cancer
1986; 57: 721–727.
mild and easily manageable, and most of the chest tubes
Antony VB, Rothfuss KJ, Godbey SW, Sparks JA, Hott
JW. Mechanism of tetracycline-hydrochloride-induced
The present study confirms that patients with pleural
pleurodesis. Am Rev Respir Dis
1992; 146: 1009–1013.
effusion undergoing pleurodesis have a median survival
Vargas FS, Wang NS, Teixeira LR, Carmo AO, SilvaLMMF, Light RW. Corynebacterium parvum versus
of about 12 months, with a mean time to recurrence of
tetracycline as pleural sclerosing agents in rabbits. Eur
30 days. Tetracycline and bleomycin are equally effec-
1995; 8: 2174–2177.
tive. It is remarkable that not only patients with com-
Vargas FS, Wang NS, Lee HM, Gruer SE, Sassoon CSH,
plete responses benefit from sclerotherapy, since many
Light RW. Effectiveness of bleomycin in comparison to
of those with partial responses never become failures
tetracycline as pleural sclerosing agent in rabbits. Chest
they never need retreatment).
With similar efficacy and toxicity, the choice of one
Martínez-Moragón E, Aparicio J, Sanchis J, et al
agent over the other should take into account other fac-
Pleurodesis con tetraciclinas en el tratamiento del der-
tors such as drug availability, economic costs and med-
rame pleural maligno. Estudio retrospectivo de 91 casos.
ical skill. At our institution, bleomycin costs are 2.6
Med Clin (Barc)
1993; 101: 201–204.
Republic of the Philippines City Government of Isabela Basilan Email Add: Tel. No. 062-200-7292 REQUEST FOR QUOTATION (RFQ) Procurement of Essential Drugs and Medicines (Lot 3) The Government of the Philippines has received a Grant from the European Union Commission, through the World Bank acting as the Administrator, towards the cost of the Mindanao Health S
Gottes Reich verändert die Gesellschaft Röm 14,17;Mt 5,13-16 Denn das Reich Gottes ist nicht Essen und Trinken, sondern Gerechtigkeit und Frieden und Freude in dem heiligen Geist. Röm 14,17 Ihr seid das Salz, das die Welt vor dem Verderben bewahrt. Aber so, wie das Salz nutzlos ist, wenn es seine Kraft verliert, so seid auch ihr nutzlos, und man wird über euch hinweggehen, wenn ih