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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1228-1233 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.164 Prospective Randomized Trial of Intrapleural Bleomycin Versus Interferon Alfa-2b via Ultrasound-Guided Small-Bore Chest Tube in the Palliative Treatment of Malignant Pleural EffusionsFrom the Section of Interventional Ultrasound and Department of Internal Medicine, St Anna Hospital, Ferrara; and the Division of Oncology, City Hospital, Rimini, Italy Address reprint requests to Sergio Sartori, MD, Section of Interventional Ultrasound, Department of Internal Medicine, St Anna Hospital, corso Giovecca 203, I-44100 Ferrara, Italy; e-mail: srs{at}unife.it
PURPOSE: To compare bleomycin pleurodesis and immunotherapy with intrapleural interferon alfa-2b (IFN) in the palliation of malignant pleural effusions. PATIENTS AND METHODS: One hundred sixty patients with rapidly recurrent malignant pleural effusion were randomly assigned to intrapleural bleomycin (83 patients) or IFN (77 patients). A 9-French intrapleural catheter was placed under sonographic guidance, and pleural effusion was completely drained before starting the treatment. Bleomycin 0.75 mg/kg was administered as a single dose. An additional dose was given if daily fluid output did not drop to less than 100 mL/d within 3 days. IFN 1 million units/10 kg was administered for six courses at 4-day intervals. Thirty-day and long-term responses were evaluated under the intention-to-treat principle. RESULTS: Thirty-day response was 84.3% in the bleomycin arm and 62.3% in IFN arm (P = .002). Median time to progression was 93 days (range, 12 to 395 days) in bleomycin group, and 59 days (range, 7 to 292 days) in the IFN group (P < .001). Median survival was 96 days (range, 15 to 395) and 85 days (range, 16 to 292) in the bleomycin and IFN groups, respectively. Twenty-three patients received two doses of bleomycin, as their daily fluid output remained higher than 100 mL after the first dose. Thirteen of them had complete response, which lasted until death. CONCLUSION: Intrapleural bleomycin is more effective than IFN and is a valid option for the palliative treatment of massive, rapidly recurrent malignant pleural effusions. The administration of a second dose of bleomycin to patients not responding to the first one can remarkably improve the overall outcome of the treatment.
Malignant pleural effusions are a common complication of end-stage malignancy, severely impairing quality of life. Most effusions do not respond to systemic chemotherapy, and the treatment is generally palliative. Symptomatic relief can be achieved by drainage of pleural fluid, but rapid recurrence of the effusion often occurs. If life expectancy is not too short, pleurodesis is the most recommended treatment.1,2 Complete drainage of pleural effusion by tube thoracostomy before instillation of sclerosant agents is considered to play a key role in successful pleurodesis.1-3 Traditionally, large-bore chest tubes (24 to 32 French) have been employed,1,3-5 but imaging-guided, small-bore catheters (10 to 14 French) have been proven to have similar success rates, with lower patient discomfort.6,7 Among the wide variety of sclerosing agents used to produce pleurodesis,1,2,8 talc is considered the most effective.5,8-12 However, severe complications can occur,9,13,14 and the use of talc as a first-choice agent is still controversial.15,16 Bleomycin is the most widely used antineoplastic agent for pleurodesis, and intrapleural instillation is usually well tolerated.2,17 Success rates ranging from 70% to 85% have been reported,1,2,5,6,18 and two randomized trials comparing talc and bleomycin did not demonstrate any significant difference between the two agents.5,19 Since pleural exudate cells are thought to play a role in the host defense against cancer cells, intracavitary biologic response modifiers have also been used to control malignant effusions.20 Some trials investigating intrapleural interferon alfa or beta (hereafter, "IFN") reported success rates ranging from 35% to 70%,21-23 and Wilkins et al obtained a 100% success rate administering IFN-  after complete drainage of the effusion by closed chest tube thoracostomy.24 However, all these trials were uncontrolled and recruited small numbers of patients, and many authors highlighted the need of larger, randomized, controlled studies to verify these promising results.2,20,23,24
This randomized study was planned to compare the palliative efficacy of intrapleural bleomycin and recombinant IFN-
Between 1995 and 2002, 160 patients (59 males and 101 females; age, 38 to 82 years; mean age, 59 years) with rapidly recurrent metastatic pleural effusion due to end-stage malignancies refractory to systemic treatment were enrolled. Sixty-one patients had lung cancer; 54, breast cancer; 16, ovarian cancer; 12, renal cancer; and 17, other cancers. Eligibility criteria were the following: cytologically proven malignant pleural effusion, requiring at least two thoracenteses in the preceding 4 weeks; at least 3 L of fluid drained in the preceding 4 weeks; radiographic demonstration of adequate pulmonary re-expansion after thoracentesis; last systemic treatment administered at least 6 weeks before the enrollment; no further chemotherapeutic option; Karnofsky performance status over 40; and written informed consent to participate in the study. The patients were randomly assigned to intrapleural treatment with bleomycin or recombinant IFN when chest x-ray and ultrasound documented pleural effusion recurrence after the last thoracentesis, immediately before the placement of the thoracic catheter. Random assignment was performed using computer-generated randomization lists. The study was designed according to the principles of the Declaration of Helsinki and was approved by our local ethical committee. In all patients, a 9-French thoracic catheter (Pleurocath; Plastimed, Saint-Leu-La-Foret, France) was placed into the pleural space in the posterior axillary line under ultrasound guidance. The catheter was then connected to a three-way stopcock and a drainage bag. Pleural fluid was drained without using any suction apparatus, until ultrasound examination of the chest showed complete disappearance of the effusion. If ultrasound examination showed loculations, the patient underwent ultrasound-guided thoracentesis. After radiographic demonstration of lung re-expansion, bleomycin 0.75 mg/kg in 50 mL of normal saline, or IFN 1 million U/10 kg in 200 mL of normal saline were instilled into the pleural space via the chest tube. The tube was then clamped for 2 hours, and the patients were invited to change positions every 15 minutes. Bleomycin was usually administered as a single dose, but an additional dose was given if daily fluid production did not drop to less than 100 mL/d within 3 days of the first dose. IFN was administered for six courses at 4-day intervals, according to a prior schedule reporting good results in malignant peritoneal effusions.25 The chest tube was removed 24 to 48 hours after the last administration of the drugs, and the patients were monitored weekly for fluid recurrence with clinical and ultrasound examination of the chest. Thirty-day response was assessed according to the criteria of Paladine et al.26 Complete response was defined as no reaccumulation of fluid; partial response, as asymptomatic fluid recurrence less than 50% of the original effusion, not requiring thoracentesis; no response, as fluid recurrence greater than 50% of the original effusion, requiring thoracentesis. Global response was defined as complete response plus partial response. Treatment failure was defined as no response, plus deaths before 30 days, plus dropouts. Thirty-day responders were then sonographically monitored every 2 weeks until death or progression, defined as fluid recurrence requiring thoracenthesis. Time to progression was defined as the time from the chest tube removal to the first posttreatment thoracentesis, or the death (or the time the data were censored, April 2003) for patients not requiring thoracenthesis. The number of thoracenteses performed until death (or April 2003) was recorded for all patients, including treatment failures.
All statistical analyses were performed under the intention-to-treat principle. Thirty-day response and long-term response in the two treatment arms were compared using
All ultrasound-guided thoracic catheters were successfully placed without complications. Eighty-three patients were assigned to the bleomycin arm, and 77 were assigned to the IFN arm. The two groups were well-matched for sex, age, type of tumor, and amount of pleural fluid drained before intrapleural treatment. Table 1 shows patient characteristics.
In the bleomycin arm, sixty patients received a single dose of the drug, 23 received a further dose after 3 days, as daily fluid output remained higher than 100 mL. In the IFN arm, three patients refused to continue the treatment after two (one patient) and three (two patients) courses of therapy. Three patients in each group died within 1 month of the chest tube removal. Eighty patients in the bleomycin group, and 71 in the IFN group finished the treatment and were alive after 1 month. Thirty-day response rate was significantly higher in the bleomycin group than in the IFN group. Details of the 30-day response are reported in Table 2. Median time to progression was 93 days (range, 12 to 395 days) in the bleomycin arm, and 59 days (range, 7 to 292 days) in the IFN arm (P < .0001; Fig 1). Median survival was 96 days (range, 15 to 395 days) and 85 days (range, 16 to 292 days) in the bleomycin and IFN arms, respectively (Fig 2). On the whole, 95 thoracenteses were carried out in the bleomycin group, and 235 in the IFN group; the number of thoracenteses per patient ranged from 0 to 11 (median, 0 thoracenteses), and from 0 to 10 (median, 2 thoracenteses) in the bleomycin and the IFN arms, respectively (P < .01). Fifty-two patients in the bleomycin group and 25 in the IFN group did not require thoracentesis until death; 16 and 3, respectively, needed thoracentesis only in the last 2 weeks of life (P < .0001). Thirteen of the 23 patients needing a second dose of bleomycin had complete response, which lasted until death.
Toxicity was mild in both groups. In the bleomycin arm, self-limiting fever occurring within 12 hours of the drug administration was observed in 41 patients, vomiting was seen in 11 patients, and moderate chest pain treated with minor analgesics was present in 14 patients. In the IFN arm, a flulike syndrome occurred in 49 patients, and vomiting occurred in 10. No hematological toxicity was observed in either group.
Recurrent pleural effusions are a common clinical problem in patients with advanced neoplastic disease, and the treatment is mostly palliative. When life expectancy is not too short, pleurodesis is considered the most valid option.1-3,8 However, despite the evaluation of a wide variety of sclerosing agents, to date, no ideal agent exists. Comparison of sclerosing agents is hampered by the lack of large randomized trials, different eligibility criteria, and disparate criteria for measuring response and end points.1,2,8 Moreover, most trials are lacking in "intention-to-treat" statistical analysis, adding further problems to a proper evaluation of the actual success rates. Among the many agents historically investigated, at present, talc and bleomycin are the most widely used. Talc is considered the most effective sclerosing agent for pleurodesis, with high success rates ranging from 81% to 96%.1-3,5,8-12 However, severe and life-threatening complications such as cardiac arrhythmias, acute pneumonitis, granulomatous pneumonitis, and acute respiratory distress syndrome (ARDS) with respiratory failure have been reported.9,13,14,27,28 The incidence of major complications after talc pleurodesis has widely varied from study to study, ranging from 0.7%29 to 33%.14 In particular, the incidence of ARDS, the most worrisome complication of talc pleurodesis, is controversial,15,16,29 but it has been reported to be as high as 9% in some series, with a high mortality rate.14,28 The mechanism responsible for ARDS is unknown. An acute pneumonitis related to the systemic absorption of talc, with the subsequent elaboration of inflammatory mediators, has been hypothesized,15,16 and it has been suggested that the onset of ARDS is dose-dependent.30 However, acute respiratory failure has also been reported in 1.3% of 550 patients treated with low doses of talc,27 and several doubts and concerns remain about incidence, mechanisms, and risk of severe complications related to talc pleurodesis. For these reasons, despite its effectiveness, talc has not gained universal acceptance.6,15,16
Intrapleural bleomycin has been studied extensively as a sclerosing agent. It is well-tolerated, and its systemic absorption is limited.2,6,17,31 Despite some previous conflicting results,8 it is generally considered effective, with success rates ranging from 70% to 85%.1,2,5,6,18,32 The mechanism of action of bleomycin is not fully understood. A combination of local antineoplastic effect and fibrogenic effect has been suggested,8,23 but its ability to provoke inflammation and fibrosis has been questioned.33 Whatever mechanism of action is involved, complete drainage of the pleural effusion is considered to play a key role in successful pleurodesis, to minimize dilution of the instilled drug, and maximize the area of pleural surface exposed to its action.32,34 To this aim, imaging-guided, small-bore catheters have been proven to be as effective as large-bore chest tubes,6,7,35,36 and to date, they are recommended as a first choice for effusion drainage and pleurodesis, as they reduce patient discomfort.2 Complete drainage of the pleural effusion is also considered crucial for successful intrapleural immunotherapy with IFN.20,24 The poor results reported by prior studies investigating intrapleural IFN21,23,37 have been ascribed at least in part to incomplete fluid drainage by thoracenthesis.20,24 Conversely, when complete resolution of the effusions was achieved by chest tube drainage before instilling IFN, success rates of 70% to 100% were reported.22,24 The exact mechanism of action of intracavitary IFN is not yet fully understood. Although direct antiproliferative and cytocidal effects have been postulated and experimentally demonstrated,38,39 its immunomodulatory action is likely to play a pivotal role. Stimulation of natural-killer cells, T cells and macrophages, and the induction of other cytokines have been reported in investigations involving IFN- In our study, all patients in both treatment arms underwent ultrasound-guided placement of small-bore pleural catheter, and intracavitary treatment was administered after ultrasound examination of the chest documented complete resolution of the effusion and absence of loculations. Strict eligibility criteria were fixed to enroll only patients with quite advanced malignant disease, free from possible residual effects of the last systemic treatment, and without any option of further systemic chemotherapy. On the other hand, great attention was paid to recruit patients with rapidly recurrent, massive pleural effusions, but without any evidence of trapped lung syndrome. All these efforts were aimed at selecting a patient population suitable to compare the actual palliative efficacy of bleomycin and IFN, avoiding as much as possible the likelihood that response rates could be biased by previous or concomitant treatments, as well as by factors interfering with the action of the drugs, such as incomplete fluid evacuation or incomplete lung re-expansion. Statistical analysis was carried out under the intention-to-treat principle, as in our opinion, dropouts and early deaths should also be considered as treatment failures. Our results demonstrate that bleomycin is more effective than IFN. Short-term and long-term response rates were significantly higher, and time to progression significantly longer, in patients treated with intrapleural bleomycin. Response rate at 30 days after IFN administration was encouraging, but it dropped to less than 50% within 60 days, and just about one third of patients did not require thoracenthesis until death or the last two weeks of life. These results are similar to those of some prior studies,21,23 but they are by far worse in comparison with the two other trials that reported success rates of 70% to 100% after intrapleural IFN.22,24 We have no unequivocal explanation for such conflicting results, but the low number of patients enrolled onto these trials, the lack of an intention-to-treat analysis, and the different eligibility criteria are likely to have played some important role. Indeed, overall survival observed in these trials was more than twice as long as that observed in our study, suggesting that our strict eligibility criteria selected patients with more advanced disease and more severe effusions, scarcely suitable for nonsclerosing immunotherapy. If such an assumption is well grounded, our results suggest that intrapleural IFN is not an appropriate option for the treatment of massive, rapidly recurrent pleural effusions in end-stage malignancies. Conversely, intrapleural bleomycin can be considered an effective treatment. Thirty-day response rate was 84%, time to progression approached overall survival, and only 18% of patients needed thoracentesis before the very last stage of the disease. Interestingly, 56% of patients not responding to the first dose of bleomycin responded to a further dose. No significant toxicity was observed in these patients, and response lasted until death, which contributed significantly to the good overall outcome in bleomycin arm. Based on these observations, we think that the administration of a second dose of bleomycin should be recommended in patients not responding to the first dose. In conclusion, our study shows that intrapleural bleomycin is an effective agent for the palliative management of massive, rapidly recurrent pleural effusions in patients with advanced neoplastic disease, whereas IFN is not. Talc is considered the most effective agent for pleurodesis,1-3,5,8-12 but several concerns remain about its safety.9,13-16,27,28 Bleomycin is well tolerated,2,6,17,31 and our experience suggests that a second dose administered at a short time interval after the first dose is safe and can increase the success rate. Two randomized trials and a recent review were unable to demonstrate any significant difference in the success rates between talc and bleomycin,5,19,43 but in general, the efficacy of talc is considered slightly greater. However, it is still debated as to whether such an advantage is great enough to justify the increased risk of serious complications,15,16 and at present, the ideal agent for pleurodesis is yet to be discovered. In our opinion, bleomycin can be a valid option, awaiting large trials on humans that confirm the promising results obtained in animals by some new agents, such as transforming growth factor-ß44-46 or silver nitrate.47,48
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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48. Vargas FS, Teixeira LR, Antonangelo, et al: Experimental pleurodesis in rabbits induced by silver nitrate or talc: 1-year follow-up. Chest 119:1516-1520, 2001 Submitted September 29, 2003; accepted January 13, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Time to progression and overall survival were analyzed using the Kaplan and Meyer nonparametric test, and the outcomes in the two groups were compared using the log-rank test. The median number of thoracentesis performed in the two treatment arms until patient death (or April 2003) was compared using the nonparametric Mann-Whitney test. 
