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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 versus 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 [2]. 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 [3]. 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 [3], 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 [9], and curves were com- rodesis was significantly greater in the bleomycin-treated pared with the Mantel-Haenszel test [10]. 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 tetracycline-treat- 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 Discussion
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 References
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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.
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