Supportive Care in Cancer (2023) 31:454

https://doi.org/10.1007/s00520-023-07932-y

RESEARCH

Efficacy and safety of doxycycline versus iodopovidone for pleurodesis

through an intercostal tube in malignant pleural effusions:
a randomized trial
Vikram Damaraju1 · Inderpaul Singh Sehgal1 · Valliappan Muthu1 · Kuruswamy Thurai Prasad1 · Sahajal Dhooria1 ·
Ashutosh Nath Aggarwal1 · Ritesh Agarwal1

Received: 19 April 2022 / Accepted: 6 July 2023 / Published online: 10 July 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
Purpose The search for an inexpensive agent for chemical pleurodesis in malignant pleural effusion (MPE) continues. We
aimed to compare the efficacy and safety of iodopovidone versus doxycycline for pleurodesis in MPE.
Methods We randomized consecutive subjects with recurrent symptomatic MPE (1:1) to undergo pleurodesis with either
doxycycline or iodopovidone administered through an intercostal tube. The primary outcome was the success rate of pleu-
rodesis at 30 days. The secondary outcomes were the time to pleurodesis, chest pain (assessed using visual analog scale
[VAS]) after pleurodesis, and complications (hypotension, acute respiratory failure, empyema).
Results We randomized 52 and 58 subjects to receive either doxycycline or iodopovidone. The mean (standard deviation
[SD]) age of the study population (51% women) was 54.1 (13.6) years. Lung cancer (≥ 60%) was the most common under-
lying cause of MPE. We observed a similar frequency of success in the doxycycline vs. the iodopovidone group (complete
response: 43 (82.7%) vs. 46 (79.3%) subjects; partial response: 7 (13.5%) vs. 10 (17.2%) subjects; p = 0.3). The mean (SD)
time to pleurodesis was 1.5 (1.9) days and 1.9 (5.4) days in the doxycycline and iodopovidone groups, respectively. While the
VAS for chest pain was significantly higher with iodopovidone (mean [SD] VAS: doxycycline, 31.9 [20.9]; iodopovidone,
41.3 [21.8]; p = 0.017), it did not reach the minimal clinically important difference. The complication rates were similar
between the two groups.
Conclusion Iodopovidone was not superior to doxycycline for pleurodesis in MPE.
Trial registration number/date clinicaltrials.gov (NCT02583282) / October 22, 2015.

Keywords Indwelling pleural catheters · Tetracycline · Talc · Malignancy · Palliative care · Pleurodesis

Introduction iodopovidone, and others, [2–4]. Talc is considered the most

The primary management of malignant pleural effusion
(MPE) is symptom palliation, especially if the effusion is
recurrent [1]. The treatment options include thoracentesis,
indwelling pleural catheter, pleurodesis, pleurectomy, or
pleuroperitoneal shunting. Various agents have been used for
chemical pleurodesis, including anti-neoplastic drugs (e.g.,
nitrogen mustard, bleomycin), tetracycline derivatives, talc,
* Ritesh Agarwal
agarwal.ritesh@outlook.in
1 pleurodesis in subjects with MPE.
Department of Pulmonary Medicine, Postgraduate Institute
of Medical Education and Research (PGIMER), Sector‑12,
160012 Chandigarh, India
effective agent for pleurodesis [4]. However, the availability
and the cost of talc impede its utilization in resource-con-
strained settings. In one survey, tetracycline or doxycycline
were the preferred agents for performing pleurodesis [5]. We
have previously shown that iodopovidone has comparable
efficacy to talc in inducing pleural symphysis [6]. Further, in
a recent meta-analysis, we found iodopovidone an effective
and safe agent for pleurodesis in subjects with MPE [7]. We
hypothesized that iodopovidone pleurodesis would be supe-
rior to doxycycline in subjects with MPE. Herein, we report
the results of a randomized trial comparing two inexpensive
agents, namely iodopovidone and doxycycline, for chemical

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Methods
We conducted an investigator-initiated, single-center, paral-
lel-group, randomized controlled trial (RCT) at the Depart-
ment of Pulmonary Medicine, PGIMER, Chandigarh, India.
This study was performed per the principles of the Declara-
tion of Helsinki. The Institute Ethics Committee approved
the study protocol (Ref. No. NK/2127/Study/862). We
obtained written informed consent from all the subjects. The
trial was registered at clinicaltrials.gov (NCT02583282). We
report the study according to the consolidated standards of
reporting trials (CONSORT) [8].
Study subjects
Inclusion criteria We included subjects with recurrent symp-
tomatic MPE (malignancy proven either by pleural fluid
cytology or pleural biopsy) who showed improvement in
dyspnea following thoracentesis.
Exclusion criteria We excluded subjects with any of the fol-
lowing: (1) history of allergy to iodine or doxycycline, (2)
history of thyroid disorders, (3) failure of lung expansion
after intercostal tube insertion (trapped lung), (4) presence
of air-leak, (5) predicted life expectancy < 30 days, and (6)
failure to provide informed consent.
Randomization
We randomized consecutive subjects meeting the inclusion
criteria (1:1) to undergo pleurodesis with either iodopo-
vidone or doxycycline. The randomization sequence was
computer-generated with blocks of 20. We concealed the
sequence in sealed opaque envelopes. A physician not
directly involved in the study opened the envelope at the
time of pleurodesis. Blinding of allocation to the treatments
was not possible.
Study procedure
We followed a standard procedure of intercostal tube inser-
tion, pleural fluid drainage, anesthesia, analgesia, and post-
pleurodesis monitoring, as described previously [6]. Pleu-
rodesis was performed when the daily drainage through the
intercostal tube decreased to < 150 mL/day, and the chest
radiograph demonstrated complete lung expansion. Subjects
in the doxycycline group received 500 mg of doxycycline
(Difidox, Fusion Healthcare, Mumbai, India) dissolved in
50 mL of 0.9% saline. The iodopovidone group received
20 mL of 10% iodopovidone (Microshield, Johnson and
13
Supportive Care in Cancer (2023) 31:454
Johnson, Solan, India) dissolved in 80 mL of normal saline.
The chest tube was clamped for four hours after anesthetiz-
ing the pleura and instilling the pleurodesis agent.
We recorded chest pain on a 0–100 mm visual analog
scale marked by two anchors: no pain’ and ‘worst pain.’
The minimal clinically important difference (MCID) of VAS
for chest pain is 16 mm [9]. We used intravenous tramadol
(50 mg) for analgesia on as-needed basis after the procedure.
The chest tube was removed once the drain output decreased
to < 100 mL/day, and there was complete lung expansion on
the chest radiograph. Subjects were followed up at one week,
one, and six months.
Outcomes
Primary outcome The primary outcome was the success
of pleurodesis, defined as (1) complete success: relief of
symptoms related to the effusion and absence of fluid accu-
mulation on chest radiograph at 30 days; (ii) partial success:
relief of symptoms with reaccumulation of fluid not requir-
ing therapeutic thoracentesis; and (iii) failed pleurodesis:
reaccumulation of pleural fluid requiring therapeutic thora-
centesis or persistent drainage of > 100 mL/day requiring
repeat pleurodesis. We used doxycycline as a second agent
in those with failed iodopovidone and vice versa. Talc slurry
was used if pleurodesis failed with both agents.
Secondary outcomes The secondary outcomes were: (1)
the time to pleurodesis, defined as the interval between
instillation of the agent and removal of the chest tube; (2)
chest pain, one hour after pleurodesis; and (3) complica-
tions related to the procedure, including hypotension, fever,
acute respiratory failure, and empyema.
Sample size calculation
Based on our previous experience, iodopovidone has a suc-
cess rate of 95% for pleurodesis [6]. The success rate of
doxycycline as a pleurodesis agent has ranged from 60–85%
[10]. We assumed the success rate of doxycycline as 70%.
With a difference of 25%, we calculated a sample of 98 (88
subjects and a 10% dropout rate) subjects (power, 80%; α
error, 5%).
Statistical methods
We used the commercial statistical package SPSS (ver-
sion 26.0, IBM Inc., NY, US) for performing the statistical
analyses. Data are presented descriptively as mean (standard
deviation) or number (percentage). The difference between
continuous and categorical variables was analyzed using the
Mann–Whitney U and chi-square test (or Fisher’s exact test),
Supportive Care in Cancer (2023) 31:454
respectively. A p-value < 0.05 was considered statistically
significant.
Results
Between July 2016 and March 2021, we randomized 110
subjects (Fig. 1) to undergo pleurodesis with either doxycy-
cline (n = 52) or iodopovidone (n = 58). The baseline charac-
teristics were not different between the two groups (Table 1).
Lung cancer (≥ 60%) was the most common underlying
cause of MPE. The mean (standard deviation [SD]) age of
the study population (51% women) was 54.1 (13.6) years. At
six months, 10 subjects died in each group, while 49 were
lost to follow-up.
Primary outcome We observed a complete response in 43
(82.7%) and 46 (79.3%) subjects in the doxycycline and the
iodopovidone groups, respectively (Table 2). Partial suc-
cess was noted in seven (13.5%) subjects in the doxycycline
group and 10 (17.2%) in the iodopovidone group. There was
pleurodesis failure in two subjects each, in the two groups.
The two subjects in the doxycycline group required a sec-
ond session of pleurodesis with iodopovidone, while one
required a third attempt with talc. The two subjects in the
iodopovidone group achieved pleural symphysis with a sec-
ond attempt using doxycycline.
Secondary outcomes The mean (SD) VAS for chest pain
was 31.9 (20.9) mm and 41.3 (21.8) mm in the doxycycline
and iodopovidone groups, respectively. While the difference
Fig. 1  CONSORT diagram
depicting the flow of partici-
pants in the study
Page 3 of 6 454
was statistically different, it did not reach the MCID. The
time to pleurodesis and other complication rates were not
different in the two groups (Table 2). None of the subjects
had hypotension or acute respiratory failure associated with
the administration of either agent.
Discussion
We found iodopovidone not superior to doxycycline for
chemical pleurodesis in subjects with MPE. The success
rate (complete or partial) was approximately 96% in both
groups. The number of pleurodesis attempts was also not
statistically different between the two groups. Chest pain
was seen in most of the subjects in our study. The subjects
in the iodopovidone group had higher VAS scores for pain
though it did not meet the MCID criteria. There were no
major adverse events confirming the safety of both these
agents. The current study is the first RCT comparing iodopo-
vidone and intravenous doxycycline preparation.
Only a few studies have compared iodopovidone with tet-
racycline derivatives (Table 3). Two studies (one RCT and
one retrospective observational study) compared iodopo-
vidone with doxycycline [11, 12]. Both these studies used
powder from oral doxycycline capsules for intrapleural
instillation. The pleurodesis success rates were similar
in the two groups. Two other RCTs have compared pleu-
rodesis outcomes between iodopovidone and tetracycline
[13, 14]. Both studies used the oral preparation of tetra-
cycline. The pleurodesis success rates were not different
between the groups. The success rates with iodopovidone
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454 Page 4 of 6 Supportive Care in Cancer (2023) 31:454

Table 1  Baseline characteristics Doxycycline (n = 52) Iodopovidone (n = 58)

of the study population
Age, years 55.6 (13.2) 52.7 (14.0)
Male sex 25 (48.1%) 29 (50%)
Etiology of pleural effusion
Carcinoma of the lung 34 (65.3%) 40 (68.9%)
Adenocarcinoma 29 (55.8%) 35 (60.3%)
Squamous cell carcinoma 1 (1.9%) 2 (3.4%)
Not otherwise specified 4 (7.7%) 3 (5.2%)
Other causes
Carcinoma of the ovary 7 (13.5%) 2 (3.4%)
Unknown primary 4 (7.7%) 5 (8.6%)
Carcinoma of the breast 1 (1.9%) 7 (12.1%)
Renal cell carcinoma 1 (1.9%) 1 (1.7%)
Thymic cell carcinoma 2 (3.8%) 0 (0%)
Carcinoma of the cervix 0 (0%) 1 (1.7%)
Papillary thyroid carcinoma 1 (1.9%) 0 (0%)
Malignant melanoma 0 (0%) 1 (1.7%)
Carcinosarcoma 1 (1.9%) 0 (0%)
Gastrointestinal malignancy 1 (1.9%) 0 (0%)
Synovial cell sarcoma 0 (0%) 1 (1.7%)
Dose of lignocaine, mg 93.9 (50.8) 84.4 (44.6)
Dose of tramadol, mg 71.1 (26.8) 70.6 (40.8)
Number of pleurodesis attempts
One 50 (96.2%) 56 (96.6%)
Two 1 (1.9%) 2 (3.4%)
Three 1 (1.9%) 0 (0%)

All values are number (%) or mean (standard deviation) unless otherwise stated

Table 2  Study outcomes

Doxycycline (n = 52) Iodopovidone (n = 58) Estimate difference (95% CI) P value

Primary outcome
Success of pleurodesis 50 (96.2%) 56 (96.6%) −0.004 (−0.098 to 0.083) 0.30
Complete success 43 (82.7%) 46 (79.3%)
Partial success 7 (13.5%) 10 (17.2%)
Secondary outcomes
Duration of ICTD after pleu- 1.5 (1.9) 1.9 (5.4) −0.4 (−1.97 to 1.17) 0.55
rodesis, days
VAS for pain, mm 31.9 (20.9) 41.3 (21.8) −9.4 (−17.49 to −1.31) 0.02
Complications 0.58
Fever 1 (1.9%) 3 (5.3%) −0.03 (−0.12 to 0.05)
Empyema 1 (1.9%) 2 (3.4%) −0.01 (−0.09 to 0.07)
Chest pain 50 (96.2%) 57 (98.3%) −0.02 (−0.11 to 0.05)

All values are number (%) or mean (standard deviation) unless otherwise stated
ICTD intercostal tube drainage, VAS visual analog scale

and tetracyclines ranged from 67 to 93% and 80% to 93%, compared to previous studies could be attributed to the use
respectively. The efficacy of iodopovidone pleurodesis in of intravenous rather than oral formulation.
the current study was like a previous study from our center What are the clinical implications? Doxycycline or
[6]. The higher success rate of doxycycline in the current iodopovidone can be used safely for chemical pleurodesis

13
Supportive Care in Cancer (2023) 31:454 Page 5 of 6 454

in subjects with MPE. The cost of sterile talc in India for

2.8%

3.4% 1.9%
10%
D/T

NA

NA
Empyema
pleurodesis is about 4000 INR (53 USD) for four grams. In
comparison, the cost of doxycycline (for 500 mg intravenous

NA

NA
0%

27.8% 0%
IP
preparation) and iodopovidone (100 ml of 10% preparation)
is approximately 1,200 INR (16 USD) and 100 INR (1.3

96.6% 96.2% 98.3% 96.2% 5.3% 1.9%

33.3% 33% 13%
60% 50% 30%
D/T

NA
USD), respectively. Given the equal efficacy and lesser cost,
iodopovidone may be used as the first agent for pleurodesis
Fever

NA
4%
in a resource-constrained setting.
IP

Finally, our study has limitations. The current study was

10%
25%
D/T

a single-center study with a relatively small sample size.

Chest pain

Ideally, the study should have had three arms (iodopovidone

13%
50%

93.4% 93.3% 10%

76% 80.6% 48%
vs. doxycycline vs. sterile talc). Due to logistical constraints,
IP

we chose only two arms. We also defined success (complete

or partial) at 30 days. However, many recent studies have
66.7% 80%
80% 90%
D/T

evaluated the success of pleurodesis at 90 days [4, 15]. A

Success

higher proportion of subjects with ovarian carcinoma in the

IP

doxycycline arm and a higher frequency of subjects with

D Doxycycline, ICTD intercostal chest tube drain, IP iodopovidone, NA not available, RCT​randomized controlled trial, T tetracycline

breast carcinoma in the iodopovidone group might have

10, 20 mL 10% 10, 7 mg/kg (100 mg capsules) doxycycline

58, 20 mL 10% 52, 500 mg intravenous preparation doxy-

underestimated or overestimated the efficacy of either agent.

In conclusion, the results of this study suggest that iodop-
ovidone is not superior to doxycycline for chemical pleu-
15, 20 mL 5% 15, 1000 mg capsule tetracycline
Saleh, 2020, Observational study, Egypt IP: ICTD - 22, Pigtail – 3 25, 20 mL 10% 36, 500 mg doxycycline capsule

rodesis in MPE.
15, 20 mL 10% 15, 500 mg tetracycline
Iodopovidone Tetracyclines (n), dose

Author contributions VD: data collection, data analysis, manuscript

preparation, and manuscript review.
IPS: data collection, data analysis, manuscript review.
VM: data collection and manuscript review.
capsule

cycline

KTP: data collection and manuscript review.

SD: data collection and manuscript review.
ANA: data collection and manuscript review.
RA: study design, data collection, manuscript preparation, and
group (n), dose

manuscript review.

Data Availability Data will be made available on request with the cor-
responding author.
Table 3  Studies comparing iodopovidone and tetracycline derivatives

Declarations
D: ICTD - 12, Pigtail - 24

Ethics approval This study was performed in line with the principles
Tube thoracostomy
Tube thoracostomy

Tube thoracostomy

Tube thoracostomy
Type of procedure

of the Declaration of Helsinki. The institute ethics committee approved

the study protocol (Ref. No. NK/2127/Study/862).

Consent to participate We obtained written informed consent from

all the subjects.

Consent for publication N/A.

Author, year, study design, country

Conflicts of interest The authors have no relevant financial or non-

Omoregbee, 2021, RCT, Nigeria

financial interests to disclose.

Shouman, 2012, RCT, Egypt
Bakr, 2013, RCT, Egypt

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