Malignant pleural effusion (MPE) is a common and distressing complication of advanced malignancy, occurring in approximately 15% of all cancer patients, and significantly contributing to morbidity and reduced quality of life [1]. The condition is most frequently associated with metastatic lung and breast cancers, although lymphomas and gynaecologic malignancies are also notable contributors [2]. MPE is often indicative of poor prognosis, with median survival ranging from 3 to 12 months depending on tumour type and patient performance status [1].

The pathophysiology of MPE involves the infiltration of the pleura by malignant cells, leading to disruption of lymphatic drainage, increased capillary permeability, and inflammatory cytokine-mediated effusion formation [3,4]. Management is largely palliative, focusing on symptom relief—primarily dyspnoea—and includes repeated thoracentesis, indwelling pleural catheter (IPC) placement, or chemical pleurodesis [3].

Pleurodesis remains a widely accepted intervention for patients with recurrent, symptomatic effusions who are unsuitable for long-term catheter drainage or thoracoscopic surgery. The procedure aims to obliterate the pleural space by promoting fibrosis through intrapleural administration of a sclerosing agent [3,5]. Although talc is considered the most effective sclerosing agent [6], its use is limited by availability, potential complications (e.g., acute respiratory distress syndrome), and cost—particularly in resource-constrained settings.

Consequently, alternatives such as Bleomycin and Povidone-Iodine have gained prominence. Bleomycin, an antineoplastic agent, has shown moderate efficacy in pleurodesis but is expensive and not readily available in all settings [5]. In contrast, Povidone-Iodine, an antiseptic with sclerosant properties, is inexpensive, widely available, and has demonstrated comparable efficacy and safety profiles in several observational studies and small trials [5,7].

Despite these advantages, direct comparisons between Bleomycin and Povidone-Iodine in randomized clinical settings remain limited, particularly in the Indian subcontinent. Hence, the present study was designed to compare the efficacy, safety, and outcome of Bleomycin and Povidone-Iodine pleurodesis in patients with malignant pleural effusion using a prospective randomized trial design.

OBJECTIVES

This study aimed to compare the efficacy, safety, and clinical outcomes of Bleomycin versus Povidone-Iodine pleurodesis (PIP) when administered via chest tube in the palliative management of recurrent malignant pleural effusion (MPE).

Specific Objectives

1. To evaluate the success rate of Povidone-Iodine as a sclerosing agent for pleurodesis.
2. To evaluate the success rate of Bleomycin as a sclerosing agent for pleurodesis.
3. To perform a comparative analysis of the efficacy of these two agents in achieving sustained pleurodesis.
4. To compare the safety profiles and incidence of procedure-related adverse effects between the two agents.

Study Design and Setting

This was a prospective, randomized, comparative clinical study conducted at the Department of Respiratory Medicine, Medical College and Hospitals, Kolkata, between January 2020 and July 2021. The study included a 6-month follow-up period for all participants post-pleurodesis.

Study Population

The study enrolled 100 patients with malignant pleural effusion (MPE) who were admitted with symptomatic dyspnoea due to recurrent pleural fluid accumulation. Eligible patients were randomized in a 1:1 ratio into two groups (n = 50 each) to undergo chemical pleurodesis with either Povidone-Iodine or Bleomycin.

Inclusion Criteria

• Patients with histologically or cytologically confirmed MPE
• Presence of symptomatic dyspnoea significantly affecting quality of life
• Post-thoracentesis drainage < 100 mL/day
• Expected survival ≥ 6 months
• No evidence of trapped lung on imaging or bronchoscopy
• Provided informed written consent

Exclusion Criteria

• Evidence of trapped lung
• Known allergy to either Povidone-Iodine or Bleomycin
• Poor performance status or life expectancy < a few weeks

Randomization and Intervention

Patients were randomized using a computer-generated sequence into:

• Group A: Received pleurodesis with Povidone-Iodine
• Group B: Received pleurodesis with Bleomycin

Randomization was unblinded due to the nature of the interventions.

Pleurodesis Protocol

Pleurodesis was performed via an intercostal chest tube following adequate pleural fluid drainage. Once drainage was <100 mL/day:

• Group A (Povidone-Iodine): Received a mixture of 20 mL of 10% Povidone-Iodine, 10 mL of 2% lignocaine, and 30 mL of normal saline.
• Group B (Bleomycin): Received 60 units of Bleomycin diluted in 50 mL of sterile water.

Following instillation:

• The chest tube was clamped for 2 hours to allow sclerosant contact.
• The tube was then reopened and maintained for 24 hours, post which chest X-ray was used to confirm lung re-expansion.

Outcome Measures

Primary Outcome

• Efficacy of pleurodesis at 6 months, categorized as:

O Complete Response: No re-accumulation of pleural fluid and resolution of dyspnoea

O Partial Response: Small, asymptomatic re-accumulation

O Failure: Recurrent, symptomatic effusion requiring further intervention

Secondary Outcomes

• Change in dyspnoea score (clinical assessment)
• Radiologic recurrence on chest X-ray
• Incidence of adverse effects (e.g., fever, chest pain, allergic reactions)
• Need for repeat pleural interventions
• Cost comparison

Follow-up and Assessment

Patients were followed up clinically and radiologically for up to 6 months post-procedure. Chest radiographs were repeated at 1 month and 6 months, or earlier if recurrence was clinically suspected. Symptom relief and adverse events were monitored at each visit.

1. Study Cohort

A total of 100 patients diagnosed with malignant pleural effusion (MPE) were enrolled and randomized into two equal groups (n = 50 each) to receive pleurodesis with either Povidone-Iodine or Bleomycin. All patients completed the intervention and the scheduled six-month follow-up period, with no cases of attrition or loss to follow-up.

Baseline demographic and clinical characteristics were statistically comparable between the two groups. The mean age of participants was similar, with the majority (67%) aged over 60 years (p = 0.832). Gender distribution was also balanced; 63% of the total cohort were male, and 37% female (p = 0.836). Regarding smoking status, 32% of patients were current smokers, 29% were ex-smokers, and 39% were non-smokers, with no significant difference between groups (p = 0.173).

Comorbidities were common in the study population, affecting 64% of participants. The most frequently observed comorbid condition was a combination of hypertension and chronic obstructive pulmonary disease (HTN + COPD), accounting for 21% of cases overall. Notably, a significantly higher proportion of patients in the Povidone-Iodine group had no comorbidities compared to the Bleomycin group (46% vs. 26%, p = 0.032).

Baseline characteristics are summarized in Table 1, and comparative age and sex distributions are depicted in Figure 1.

Table 1. Baseline Demographics and Clinical Characteristics of the Study Population

                   *Statistically significant at p < 0.05.

2. Clinical Presentation and Symptomatology

At presentation, the most common symptom among study participants was dyspnoea, reported in 92% of patients overall (94.0% in the Povidone-Iodine group vs. 90.0% in the Bleomycin group; p = 0.543). Cough was present in 43% of all patients, with a significantly higher prevalence in the Povidone-Iodine group compared to Bleomycin (54.0% vs. 32.0%, p = 0.026), suggesting a potential difference in pre-pleurodesis respiratory symptom burden.

Other symptoms—including fever, chest pain, pallor, and clubbing—were observed at comparable rates between the two groups, with no statistically significant differences. Fever was reported in 48.0% of the Povidone-Iodine group and 36.0% of the Bleomycin group (p = 0.224), while chest pain affected 52.0% and 46.0%, respectively (p = 0.548). Minor signs such as cyanosis, pedal oedema, and jugular venous pressure (JVP) abnormalities were infrequent and similarly distributed.

Notably, cyanosis was significantly more common in the Povidone-Iodine group (34.0%) compared to the Bleomycin group (10.0%) with a p-value of 0.004, although its clinical impact in terms of oxygenation or treatment outcomes was not directly assessed.

Lymphadenopathy, primarily in the supraclavicular and jugular regions, was documented in 48% of patients, again with no significant intergroup difference.

These findings are summarized in Table 2, and the symptom distribution is visually represented in Figure 2.

Table 2. Clinical Presentation and Symptomatology

*Statistically significant at p < 0.05.

3. Pleural Effusion Characteristics

The majority of patients (70%) presented with right-sided pleural effusion, with no statistically significant difference between the Povidone-Iodine and Bleomycin groups (68.0% vs. 72.0%, respectively; p = 0.669). Massive effusions, defined as occupying two-thirds or more of the hemithorax, were the predominant radiographic finding, accounting for 66.0% of cases overall (64.0% in Povidone-Iodine group vs. 68.0% in Bleomycin group; p = 0.659).

Analysis of pleural fluid appearance revealed that straw-coloured effusions were most common in both groups, seen in 52.0% of all patients. However, turbid yellow effusions were observed exclusively in the Povidone-Iodine group (10.0% vs. 0.0%), resulting in a statistically significant difference in distribution of fluid appearance (p = 0.039).

The pleural fluid cell counts were predominantly low, with most samples containing fewer than 1500 cells/mm³. Differential cell count patterns were similar between the groups and were not statistically significant (p = 0.357).

These findings are summarized in Table 3, and the distribution of pleural effusion features is visually represented in Figure 3.

Table 3. Pleural Effusion Characteristics

      *Statistically significant at p < 0.05.

4. Treatment Efficacy

The primary outcome of the study was the success rate of pleurodesis at the end of a six-month follow-up period. A complete response—defined as the absence of re-accumulated pleural fluid on imaging and sustained symptom relief—was achieved in 75.0% of patients in the Povidone-Iodine group and 79.0% in the Bleomycin group. This difference was not statistically significant (p = 0.783), suggesting comparable efficacy between the two agents in achieving effective pleurodesis.

Partial responses, where minimal radiological reaccumulation occurred without significant clinical symptoms, were observed in 20.0% of patients in the Povidone-Iodine group and 19.0% in the Bleomycin group. Pleurodesis failure—defined by symptomatic fluid recurrence requiring repeat intervention—was recorded in 5.0% of patients in the Povidone-Iodine arm and 2.0% in the Bleomycin arm. Again, these differences did not reach statistical significance.

Importantly, improvement in dyspnoea, assessed one-month post-procedure, was significantly greater in the Bleomycin group (p = 0.002). This outcome remained statistically significant even after adjusting for age, chest pain, and pre-pleurodesis dyspnoea scores using a general linear model. This suggests that while both agents were comparable in radiological efficacy, Bleomycin may offer superior early symptomatic relief.

No mortality was observed during the six-month follow-up period in either group. The need for repeat pleural interventions was limited to patients classified as pleurodesis failures.

Outcome data are summarized in Table 4 and visually depicted in Figure 4.

Table 4. Treatment Efficacy Outcomes at 6 Months

       *Statistically significant at p < 0.05.

5. Symptom Relief and Functional Outcomes

Symptomatic relief—particularly improvement in dyspnoea—was a key clinical endpoint. One month after pleurodesis, patients in the Bleomycin group reported significantly greater improvement in dyspnoea compared to those in the Povidone-Iodine group. This was consistent both on subjective assessment and on follow-up clinical evaluation. The difference was statistically significant (p = 0.002), suggesting a possible advantage of Bleomycin in early post-procedure functional recovery.

A general linear model (GLM) was applied to control for potential confounders including age, pain scores, and baseline dyspnoea. After adjustment, the superiority of Bleomycin in dyspnoea improvement remained statistically significant, indicating that the observed difference was not due to baseline imbalances.

There were no statistically significant differences between the groups regarding other functional symptoms, including pain at the procedure site, fatigue, or sleep disturbance. Both groups experienced improved respiratory comfort and daily functioning within the first month following intervention.

These results reinforce that while the overall pleurodesis success rate was comparable, Bleomycin may confer faster symptomatic benefit, particularly in terms of dyspnoea relief—a central concern in patients with advanced malignant effusions.

6. Adverse Events and Safety

Both sclerosing agents were well tolerated overall, with no serious adverse events or procedure-related mortality reported in either group during the six-month follow-up period. The majority of patients experienced only mild and transient side effects, which resolved with symptomatic treatment and did not necessitate discontinuation of therapy.

The most commonly reported adverse effects were chest pain and fever, occurring in both groups at comparable rates. Chest pain was reported by 24.0% of patients in the Povidone-Iodine group and 20.0% in the Bleomycin group (p = 0.639), while fever was noted in 22.0% and 18.0%, respectively (p = 0.620). These differences were not statistically significant.

Mild local irritation at the site of chest tube insertion and transient hypotension were observed infrequently and did not differ meaningfully between groups. Importantly, no allergic reactions, ARDS, or procedure-related infections were encountered, affirming the safety of both agents in this setting.

The data on adverse events are summarized in Table 5.

Table 5. Adverse Events by Treatment Group

      *No statistically significant differences between groups (p > 0.05 for all applicable comparisons).

Table 6. Summary of Key Statistical Comparisons

                     *Statistically significant at p < 0.05.

This study demonstrated that both Povidone-Iodine and Bleomycin are effective and safe agents for pleurodesis in patients with malignant pleural effusion (MPE), with no significant difference in overall success rates. These findings are in agreement with those of Alavi et al., who found comparable efficacy between Povidone-Iodine and Bleomycin in inducing pleurodesis, concluding that both agents are viable options in palliative management of MPE [8].

Similarly, Bakr et al. conducted a comparative evaluation of multiple agents and noted that both Povidone-Iodine and Bleomycin achieved satisfactory pleurodesis outcomes, with minimal complications [9]. Our result showing a pleurodesis success rate of 75% for Povidone-Iodine and 79% for Bleomycin echoes their findings.

In a more recent study by Bagheri et al., Povidone-Iodine achieved a 76.6% complete response rate, closely approximating the 75% rate observed in our study, thereby supporting its utility as a cost-effective alternative to Bleomycin [10]. The current study also observed significantly better early dyspnoea relief with Bleomycin, which was not explicitly discussed by Bagheri et al., though they did report slightly better subjective comfort in Bleomycin-treated patients.

Kahrom et al. evaluated the safety profile of Povidone-Iodine and confirmed its overall tolerability, with no severe adverse events—a finding consistent with our experience, where both agents were well tolerated without major complications [11].

Fahad et al. reported slightly higher success rates with Bleomycin (83%) compared to Povidone-Iodine (70%), yet also emphasized the greater availability and affordability of Povidone-Iodine, a theme which aligns with our real-world observations though formal cost analysis was not performed [12].

In another study from Indonesia, Murni et al. also found no statistically significant difference in efficacy between the two agents, but reported that Bleomycin yielded slightly faster radiological resolution of effusion, which parallels our findings of greater dyspnoea improvement at one month in the Bleomycin group [13].

Elsayed and Alawady compared three agents—Bleomycin, doxycycline, and Povidone-Iodine—and noted that although Bleomycin achieved the highest response rate, Povidone-Iodine remained highly effective and well-tolerated, especially in patients with financial constraints [14]. These findings reinforce the real-world relevance of Povidone-Iodine, particularly in public health systems.

Sobhy also supported the use of Povidone-Iodine, citing its favorable safety profile and low recurrence rate, with results consistent with our study’s 5% pleurodesis failure rate in the Povidone-Iodine group [15].

Muthu et al. provided a more robust analysis through a systematic review and meta-analysis, concluding that Povidone-Iodine is a safe and moderately effective pleurodesis agent. Their pooled data support its use when more expensive agents are unavailable or impractical [16]. This meta-analytic evidence further supports our interpretation that Povidone-Iodine represents a practical and effective pleurodesis agent in resource-limited settings.

Lastly, Ibrahim et al. compared Povidone-Iodine and talc pleurodesis and found both agents comparably effective, though talc was associated with slightly more complications. This positions Povidone-Iodine not only as an alternative to Bleomycin but also to talc in certain clinical scenarios [17].

Limitations

This study was conducted at a single centre with a relatively modest sample size, which may limit the generalizability of the findings. Although randomization was performed, blinding was not feasible due to the nature of the agents used. Additionally, no formal cost-effectiveness analysis was included, despite economic considerations being an important factor in real-world treatment selection. Objective dyspnoea scoring tools (e.g., mMRC or Borg scale) were not uniformly applied, which may have influenced the subjective assessment of symptom improvement.

This study demonstrates that both Povidone-Iodine and Bleomycin are effective, safe, and clinically viable agents for pleurodesis in patients with malignant pleural effusion. While no significant difference was observed in pleurodesis success or complication rates, Bleomycin was associated with greater early dyspnoea relief. However, Povidone-Iodine offers a distinct cost and accessibility advantage, making it an attractive alternative in low-resource settings. These findings support the continued use of Povidone-Iodine as a practical and economical agent in the palliative management of MPE, particularly where Bleomycin is unavailable or unaffordable.

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