Phase I Trial of Intrapleural Docetaxel Administered Through an Implantable Catheter in Subjects with a Malignant Pleural Effusion

ORIGINAL ARTICLE

Phase I Trial of Intrapleural Docetaxel Administered Through an Implantable Catheter in Subjects with a Malignant Pleural Effusion David R. Jones, MD,* Matthew D. Taylor, MD,* Gina R. Petroni, PhD,† Jianfen Shu, MS,† Sandra G. Burks, BSN,* Thomas M. Daniel, MD,* and Heidi H. Gillenwater, MD‡

Introduction: Malignant pleural effusion (MPE) is a common complication in patients with advanced malignancy. This dose escalation phase I study was designed to determine the maximum tolerated dose of intrapleural docetaxel administered through an implantable catheter in subjects with MPE. Methods: Subjects with MPE (n ⫽ 15) with median age of 64.6 years and an Eastern Cooperative Oncology Group performance status of 0 to 2 at baseline were enrolled into four single dose levels of docetaxel administered intrapleurally after drainage of the pleural effusion and insertion of an intrapleural catheter. The study determined the pharmacokinetic properties, clinical response, and toxicity profile of intrapleural docetaxel. Results: All patients tolerated the therapy well and there were no significant toxicities. The majority of patients had a complete radiographic response. All patients receiving dose 100 mg/m2 or higher had a complete radiographic response. One dose-limiting toxicity was encountered in the dose 50 mg/m2. Pharmacokinetic data demonstrated peak plasma concentration of docetaxel between 30 minutes and 6 hours after infusion. Pleural exposure to docetaxel was 1000 times higher than systemic exposure. Conclusions: Single-dose intrapleural administration of doxetaxel is well tolerated in patients with MPE with minimal toxicity. The excellent clinical responses in this study after treatment with intrapleural doxetaxel suggest that further investigation is warranted. Key Words: Malignant pleural effusion, Intrapleural chemotherapy. (J Thorac Oncol. 2010;5: 75–81)

M

alignant pleural effusion is a common and debilitating complication associated with numerous types of advanced oncologic diseases. In the United States, there are more than 150,000 new cases of malignant pleural effusions (MPEs) each year. Two previous studies of MPEs demonDepartments of *Surgery, †Public Health Sciences, and ‡Medicine, University of Virginia, Charlottesville, Virginia. Disclosure: The authors declare no conflicts of interest. Address for correspondence: David R. Jones, MD, Department of Surgery, University of Virginia, Box 800679, Charlottesville, VA 22908-0679. E-mail: [email protected] Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0501-0075

strated the etiology to be lung cancer in 35 to 40% of patients and breast cancer in 23 to 26% of patients.1–3 Of the patients with MPEs, the majority are symptomatic with 96% presenting with dyspnea and 56% having complaints of pleuritic chest pain.1 The prognosis of patients with MPE is poor, with the average survival time after diagnosis being 3 to 6 months.1–3 Mortality is 54% at 1 month and 84% at 6 months.2,3 Survival is slightly longer, averaging 9.6 months, in patients whose malignant effusion is the initial manifestation of cancer.4 Patients with breast cancer and MPE commonly live for 1 year or more,5 whereas those with primary ovarian tumors have an expected survival of 9 months.3 MPEs associated with lung and gastric primary tumors have a shorter patient survival.3 Traditional treatment of MPE consists of diagnostic thoracentesis, tube thoracostomy, and intrapleural instillation of a sclerosing agent to obliterate the pleural space and prevent the reaccumulation of the effusion. Numerous sclerosing agents have been described in the literature including chemicals such as talc,6 antineoplastics agents such as bleomycin, doxorubicin, and mitomycin,7–9 biologic agents such as interferon, interleukin-2, Staphylococcus superantigen, Corynebacterium parvum, and Streptococcus pyogenes,10 –17 and antibiotics such as tetracycline, doxycycline, and minocycline.18 –20 The success of preventing the reaccumulation of the pleural effusion ranges between 40% and 100% for these treatments. Intrapleural chemotherapy for MPE has been suggested to be useful in treating the underlying malignancy in addition to providing local control of the effusion. Furthermore, the intrapleural levels of a chemotherapy agent administered into the pleural space can be significantly higher than the systemic levels. A number of chemotherapy agents have been safely administered intrapleurally (IPL) to patients with MPE, including 5-fluorouracil, bleomycin, cisplatin, carboplatin, cytarabine, etoposide, and paclitaxel. Reported pleural effusion response rates at 3 to 4 weeks range from 46 to 100%, depending on the agent.15,21–29 Because lung cancer accounts for approximately 50% of all MPEs,5 we believe that docetaxel’s efficacy in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) may extend to the treatment of MPE as

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well. This phase I study was designed to determine the safety, feasibility, and pharmacokinetics of single-dose intrapleural administration of docetaxel for the treatment of MPEs.

PATIENTS AND METHODS This study was a phase I, single institution, investigator-initiated trial. The trial was approved by the Institutional Review Board for Health Sciences Research at the University of Virginia and was conducted in accordance with the principles of the Declaration of Helsinki. All patients signed informed consent.

Patient Eligibility Patients were included who met the following criteria: age greater than 18; symptomatically, histologically, or cytologically confirmed MPE; appropriate candidate for thoracoscopic surgery; Eastern Cooperative Oncology Group performance status of 2 or less; existing peripheral neuropathy less than grade 1; absolute neutrophil count ⱖ1500/mm3, hemoglobin ⱖ8.0 g/dl, platelet count ⱖ100,000/mm3; serum creatinine ⱕ1.8 mg/dl; total bilirubin within normal limits, transaminases (alanine aminotransferase and/or aspartate transaminase) up to 1.5⫻ institutional upper limit of normal (ULN) if alkaline phosphatase is ⱕULN or alkaline phosphatase up to 2.5⫻ ULN if transaminases are ⱕULN; international normal ratio ⱕ1.5; and negative serum or urine pregnancy test for women of childbearing age. Exclusion criteria included prior ipsilateral pleurodesis, bilateral MPE, and a history of hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80.

Study Design The primary objective of the trial was to determine the maximum tolerated dose (MTD) of intrapleural docetaxel in subjects with MPE. Patients were enrolled into one of four dose cohorts (50, 75, 100, or 125 mg/m2) of three to six patients. If one of the first three patients in any cohort experience dose-limiting toxicity (DLT), the cohort was expanded to six patients. If at any time two or more patients in a cohort experienced DLT, the MTD was exceeded, and the next lowest cohort was the MTD. DLT was defined as any grade 4 investigational intrapleural chemotherapy related hematologic toxicity lasting ⬎7 days, any grade 4 investigational intrapleural chemotherapy related neutropenic fever, or any grade 3 or higher investigational intrapleural chemotherapy related nonhematologic toxicity. The starting dose of 50 mg/m2 docetaxel was 0.66 times the recommended intravenous (IV) dose for the systemic treatment of NSCLC, this being 75 mg/m2 docetaxel.

Study Conduct Before inclusion in the study, subjects provided written, informed consent to participate in the study and underwent standardized evaluations, including serum chemistries and a chest radiograph. Baseline evaluations were conducted within 14 days before the date of surgery. Subjects were admitted to the hospital on the same day as their scheduled surgical procedure. Before the procedure, a 10 ml sample of blood was obtained through a previously

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inserted intravenous or intraarterial line for pharmacokinetic analysis. Subjects underwent thoracoscopic surgery for treatment of their MPE according to the routine practice of this institution. Using a minimally invasive approach, intrapleural adhesions were lysed, and all fluid was evacuated and sampled for baseline pharmacokinetic studies. At the completion of the procedure, a small-bore closed tube thoracostomy was inserted and connected to ⫺20 cm H2O suction utilizing a pleurovac apparatus. A second soft, silicone 15.5-F intrapleural catheter (Pleurx, Denver Biomedical, Golden, CO) was inserted through a separate site and secured. The smaller, soft Pleurx catheter was subsequently used to instill the docetaxel later in the protocol. Within 4 hours postprocedure, the subjects were examined, the chest tube evaluated for evidence of an air leak, and the chest roentgenogram (CXR) examined. Subjects were premedicated with dexamethasone 8 mg PO twice a day for 3 days, starting on the day of surgery, diphenhydramine 50 mg PO or IV, and famotidine 20 mg IV or PO 1 hour before docetaxel administration. When the drainage from the chest tube was ⬍300 ml/ 24 h and there was no air leak, and the CXR demonstrated no pneumothorax or significant effusion, docetaxel (mixed in 100 ml normal saline) was IPL injected through the Pleurx catheter over 3 minutes. The chest tube and Pleurx catheter were both clamped for 4 hours after this infusion. The subjects were placed in several different positions to facilitate uniform distribution of the docetaxel. Peripheral blood and pleural fluid were obtained for subsequent pharmacokinetic analysis. The chest tube and Pleurx catheter were unclamped after the 4 hour “dwell time,” and the chest tube returned to suction. When the chest tube drainage was ⬍300 ml/24 h, the chest tube and catheter were removed. A peripheral blood sample was obtained to evaluate blood chemistry, liver function, and complete blood count. Subjects were discharged when medically stable.

Posttreatment Monitoring All subjects were seen between day 5 and day 9 postdrug administration to evaluate for adverse events. Follow-up of subjects was continued 3 weeks after the first docetaxel administration and included a CXR and routine laboratories. The CXR was compared with one obtained at baseline, and pleural effusion response was measured. Adverse events were recorded and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Subjects were followed for life and time to MPE progression and survival were documented.

Measurement of Clinical Response A chest radiograph obtained 3 weeks postdocetaxel instillation was compared with one obtained presurgery to estimate MPE response using set criteria to define complete response, partial response, stabilization, and progression. The response criteria used was based on a previous study by the Lung Cancer Study Group in a trial of intrapleural cisplatin and cytarabine in patients with MPE.30 The response criteria was as follows: (1) Complete response: total disappearance of pleural fluid or residual pleural fluid too minimal to be approachable by thoracentesis; (2) Partial response: 75% or

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greater reduction of pleural effusion compared with baseline pretreatment chest radiograph; (3) Stabilization: less than a 75% reduction and not greater than 25% increase in the amount of pleural fluid compared with baseline chest radiograph; and (4) Progression: greater than 25% increase of pleural fluid compared with baseline chest radiograph.

chemotherapy. Of these, two patients had paclitaxel after completion of the clinical trial. There was no correlation between pretrial or posttrial administration of systemic taxanes and response to intrapleural docetaxel as part of the trial. In addition, there were no delays to initiation of the posttrial chemotherapy secondary to participation in this clinical trial.

Pharmacokinetics Analysis

Toxicity

The pharmacokinetics of docetaxel was assessed in plasma and pleural fluid. Peripheral blood and pleural fluid samples were collected for pharmacokinetic analysis before docetaxel administration at the time of surgery (baseline) and at the following time points: 30 minutes, 1 hours, 6 hours, 24 hours, and 36 hours postdocetaxel instillation. Pharmacokinetic parameters were estimated using standard methodology.31

RESULTS Patient Demographics From November 2003 to February 2006, 15 patients were enrolled in the study. Table 1 illustrates the patient characteristics. Radiographically all pleural effusions were estimated to have 500 to 750 ml of intrapleural fluid at a minimum with several containing 2000 ml or more. There were nine men and six women enrolled in the study with a median age of 65 years (range, 43– 82 years). Over 50% of the patients in the study had MPE due to NSCLC. All patients had been treated with either chemotherapy or radiotherapy, although 53% (8 of 15) had had no treatment within the 2 months before enrollment in the study. As noted previously, prior treatment with docetaxel was not an exclusion criteria for the study, and as such 7 of 15 (47%) patients had docetaxel or other paclitaxel before enrolling in the study. Eighty percent (12 of 15) of patients received chemotherapy and/or radiation after completion of their intrapleural TABLE 1. Demographic and Baseline Characteristics Characteristic Age (yr) Median (range) Gender Male Female Race White African American ECOG performance status 0 1 2 Primary malignancy NSCLC Breast cancer Ovarian cancer Oral cancer Mesothelioma

No.

% 65 (43–83)

9 6

60 40

13 2

87 13

3 6 6

20 40 40

8 4 1 1 1

53.3 26.6 6.7 6.7 6.7

ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer.

There were six patients in cohort 1 (50 mg/m2) and three in each of the remaining cohorts (75, 100, and 125 mg/m2). There was one DLT in the 50 mg/m2 dosing level, which was a grade 3 infection without neutropenia. This infection was believed to be related to the presence of the intrapleural catheter used for instilling the docetaxel, which remained in place after hospital discharge. The protocol was modified to require removal of the intrapleural catheter before hospital discharge, and no further infections of this nature were observed. A second cohort of three subjects treated at the 50 mg/m2 dose experienced no DLTs. Table 2 demonstrates the number of adverse events per dose level and the severity of the adverse events. Adverse events were similar across all dose levels. Adverse events judged unrelated to the intrapleural chemotherapy were not considered DLTs regardless of their severity. All adverse events were monitored by the Data Safety Monitoring Committee for the Cancer Center at the University of Virginia.

Clinical Response After intrapleural administration of docetaxel, all patients received serial chest radiographs at 3 weeks to evaluate for the recurrence of the MPE. The clinical response for each dose level of docetaxel is shown in Table 3. Of the patients receiving 75 mg/m2 or higher doses of docetaxel, 90% demonstrated a complete response with no evidence of residual pleural effusion. All patients receiving 100 mg/m2 or more of docetaxel had a complete response to therapy. Six patients had evidence of recurrent effusion; however, only two patients required reintervention (one Pleurx catheter insertion and one thoracentesis) for symptomatic relief. All patients died in the follow-up period. Median survival time was 3.6 months (range, 1.5–17.9 months). Median survival for patients receiving 50 mg/m2 was 4.0 months (range, 1.5–17.9 months), 75 mg/m2 was 2.7 months (range, 2.1–9.6 months), 100 mg/m2 was 8.5 months (range, 7.9 –16.5 months), and 125 mg/m2 was 3.1 months (range, 1.7–7.1 months).

Pharmacokinetic Analysis Pleural fluid and plasma samples were obtained from all patients and pharmacokinetic parameters with elimination curves are displayed in Figures 1 and 2, respectively. Peak intrapleural docetaxel concentrations were achieved at approximately 60 minutes after infusion. We did note that there was a slight resurgence in intrapleural docetaxel concentrations about 24 hours postinstillation. This is thought to be secondary to mobilization of the patient with more “pockets” of docetaxel instillate being evacuated by the chest tube and then measured. Peak intrapleural docetaxel concentrations ranged from 1000 to 1600 ␮mol/l. The half-life elimination of docetaxel from the pleural space ranged from 4.1 to 5.7 hours with no

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TABLE 2. Adverse Events of Intrapleural Docetaxel Intrapleural Docetaxel Dose Levels 50 mg/m (N ⴝ 6)

75 mg/m2 (N ⴝ 3)

2

Toxicity

Grade 3–4

Grade 1–2

Grade 3–4

Grade 1–2

Grade 3–4

Grade 1–2

Grade 3–4

1 — —

— — —

1 — —

— — —

— — —

— — —

— — —

— — —

2 1 —

— — 1

— — —

— — —

— — —

— — —

— — —

— — —

1 1 — — — —

— — — — — —

— 1 2 — — —

— 1 — — — 1

— 1 — — — —

— — — — — —

1 — — 1 — —

— — — 1 1 —

—

—

—

—

—

—

—

1

1 1 — —

— — — —

2 — — —

— — — —

1 — 2 —

— — — —

— — — 1

— — — —

1 1 — —

— — — —

1 1 1 1

— — — —

— — 1 —

— — — —

— — — —

— — — —

5

—

2

—

2

—

—

—

3 3 — 6 1

— — — 1 2

— 1 1 1 —

— — — 1 1

1 2 — — —

— — — 3 —

2 — — 1 1

— — — — —

TABLE 3.

Dose (mg/m2)

Clinical Response to Intrapleural Docetaxel Complete Response Number This Response/ Total No. of Patients at This Dose

Partial Response Number This Response/ Total No. of Patients at This Dose

Stabilized Number This Response/ Total No. of Patients at This Dose

1/6 2/3 3/3 3/3 9

3/6 1/3 0/3 0/3 4

2/6 0/3 0/3 0/3 2

appreciable correlation with dose level. Pleural exposure to docetaxel as expressed by the area under the curve (AUC) ranged from 4356 to 12,617 (␮mol/l)h and inversely correlated with increasing dose levels.

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125 mg/m2 (N ⴝ 3)

Grade 1–2

Hematologic Anemia Neutropenia Thrombocytopenia Cardiovascular Tachycardia Hypotension Pulmonary embolism Pulmonary Cough Recurrent effusion Pneumothorax Hypoxia Dyspnea Pneumonia Renal Elevated creatinine Metabolic Hypocalcemia Hypophosphatemia Hyponatremia Hypokalemia Gastrointestinal Vomiting Stomatitis Nausea Dehydration Hepatic Elevated transaminases Constitutional Fever Fatigue Anorexia Pain Infection

50 75 100 125 All

100 mg/m2 (N ⴝ 3)

Peak plasma docetaxel levels were discovered from approximately 0.5 to 6 hours after intrapleural infusion with concentrations ranging from 0.17 to 0.48 ␮mol/l and without correlation to the dose level. When comparing pleural expo-

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DISCUSSION

FIGURE 1. Pleural pharmacokinetics parameters and median dose elimination curves following intrapleural docetaxel dosing.

FIGURE 2. Plasma pharmacokinetics parameters and median dose elimination curves following intrapleural docetaxel dosing.

sure and plasma exposure to docetaxel by measuring AUCs, pleural exposure to docetaxel was 1893 to 6675 times higher than systemic exposure up to 36 hours postinfusion (Figure 1).

In patients with late-stage malignancies, the development of a large MPE results in significant dyspnea, cough, fatigue, and an inability to perform activities of daily living. The goals of MPE treatment strategies are to palliate these symptoms and to prevent recurrence of the MPE. Traditional sclerosing agents such as talc, bleomycin, and tetracycline derivatives have been used for the treatment of MPEs. Although talc pleurodesis has been shown to be highly effective in apposing lung parenchyma to the chest wall, its limitations include severe pain from instillation and complications ranging from acute pneumonitis, granulomatous pneumonitis, and acute respiratory distress syndrome.32–34 Bleomycin’s success as a sclerosing agent is associated with significant variability ranging from 31 to 85%.35 Tetracycline derivatives have been effective in treating MPEs; however, multiple instillations are often necessary. The cost of using these sclerosing agents, including talc pleurodesis, for treatment of MPEs in 1995 was estimated to be between $8000 and $20,000 per treatment.35 Given the lack of large randomized prospective trials to adequately differentiate the efficacy of various sclerosing agents, no consensus has been reached regarding which agent is best. The administration of intracavitary chemotherapy for MPE has become an attractive area of investigation as it may be useful in treating the underlying malignancy in addition to providing local control of the effusion. Indeed, intraperitoneal levels 21-fold higher than serum levels have been reported after the intraperitoneal administration of cisplatin. In theory, such an approach could maximize the chemotherapeutic treatment of local disease while minimizing systemic toxicity. Limitations of this chemotherapeutic approach include the need for good dispersal throughout the pleural cavity and penetrance of only a few millimeters in patients with bulky tumors.21 Many chemotherapeutic drugs have been administered IPL including bleomycin, doxorubicin, cisplatin, etoposide, fluorouracil, and mitomycin C.36 With the exception of bleomycin, their main mechanism of action is due to their sclerosant effect on the pleura and not cytotoxicity.37 Despite bleomycin’s known cytotoxic effect, it has poor antineoplastic activity in most epithelial malignancies that result in MPE. The taxane antimicrotubule agent paclitaxel has also been safely administered IPL to patients with MPE. In a phase I trial of 18 patients, the MTD of paclitaxel was found to be 225 mg/m2, and dose-limiting toxicity involved the development of severe dyspnea.25 Subsequently, a phase II trial of intrapleural paclitaxel was then performed in 15 NSCLC patients with MPE caused by NSCLC.38 Among the 14 patients evaluable at 4 weeks, the effusion control rate was 92.9%. Similar to these results, our study demonstrates a 90% effusion control rate at 3 weeks with intrapleural docetaxel dose of 75 mg/m2 and 100% effusion control with a dose of 100 mg/m2. The pharmacological advantages of docetaxel over paclitaxel could be demonstrated by comparing the mean exposure of drug to the pleural cavity (AUC) to that of the drug exposure to plasma. As mentioned previously, paclitaxel had

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approximately a 370-fold higher exposure in the pleural cavity compared with plasma, which represents at a minimum a fivefold decrease in pleural exposure when compared with docetaxel (1893– 6675-fold pleural exposure). Nevertheless, single-dose intrapleural serum clearance of docetaxel in this study was significantly faster than the clearance of paclitaxel with the majority of drug being cleared by 20 hours after administration as compared with 48 to 96 hours with paclitaxel.38 Although speculative in nature, reasons why docetaxel may be cleared more rapidly than paclitaxel include different pharmacokinetics and differences in stability and aqueous solubility between the two compounds.26,38 Interestingly, in our study, we observed that the AUC for intrapleural docetaxel did not correlate with dose concentration. This observation has been seen with other studies of intrapleural chemotherapeutic agents including paclitaxel.38 This strongly suggest that intrapleural docetaxel may not follow dose-dependent pharmacokinetics. Possible explanations for this nonlinear pharmacokinetics could certainly include saturability of docetaxel metabolism or alternatively changes in the clearance of the drug secondary to nonlinear drug binding to tissue proteins. Further investigation needs to be performed to determine what effect this increased clearance has on the cytotoxic capacity of docetaxel systemically. The toxicity profile of intrapleural docetaxel is similar to previous phase I/II trials using paclitaxel. Constitutional symptoms were noted in 33% of patients in this study compared with 26% in the paclitaxel study.38 The incidence of anemia in this study and prior paclitaxel studies were the same at 13%. No patients developed neutropenia from treatment in this study compared with 6.7% with treatment of paclitaxel. Interestingly, 60% of the patients in this study receiving intrapleural docetaxel had modest and transient elevation in hepatic transaminases with no clinical evidence of hepatic insufficiency, as compared with 13% in the phase II trial of paclitaxel. Although efficacy was not a major end point in this phase I trial, one cannot ignore that 90% of patients receiving a single intrapleural dose of 75 mg/m2 or more had a complete response to their pleural effusion at 3 weeks after treatment. Previous work has suggested that the mechanism of antimicrotubule chemotherapeutics in the pleural cavity is due to the cytotoxic effect and less a result of the sclerosing effect.25 This hypothesis is based on the absence of significant intraabdominal adhesions at the time of exploratory laparotomy after intraperitoneal administration of paclitaxel.39 In addition, previous investigation of intrapleural paclitaxel found a 50% shrinkage in primary tumor in 1 patient of 14 patients, suggesting that intrapleural chemotherapy may have some local systemic antitumor effect.38 Clearly, this phase I study of docetaxel does not further elucidate the specific mechanism of intrapleural docetaxel therapy. Further studies appropriately powered to assess docetaxel’s efficacy after intrapleural administration are necessary. In addition, future investigation should be aimed at assessing systemic antitumor activity of docetaxel by measuring the change in size of the primary tumor after intrapleural therapy.

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In conclusion, single-dose intrapleural docetaxel for MPEs was feasible at doses of 50 to 125 mg/m2 in this phase I clinical trial. Further clinical investigation of intrapleural docetaxel is warranted to determine efficacy for treatment of MPEs.

ACKNOWLEDGMENTS Supported in part by National Institutes of Health Grant M01RR00847 to the University of Virginia General Clinical Research Center and by Sanofi-Aventis Pharmaceuticals. REFERENCES 1. Martinez-Moragon E, Aparicio J, Sanchis J, Mene´ndez R, Cruz Rogado M, Sanchis F. Malignant pleural effusion: prognostic factors for survival and response to chemical pleurodesis in a series of 120 cases. Respiration 1998;65:108 –113. 2. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med 1977;63:695–702. 3. van de Molengraft FJ, Vooijs GP. Survival of patients with malignancyassociated effusions. Acta Cytol 1989;33:911–916. 4. Monte SA, Ehya H, Lang WR. Positive effusion cytology as the initial presentation of malignancy. Acta Cytol 1987;31:448 – 452. 5. Lynch TJ Jr. Management of malignant pleural effusions. Chest 1993; 103:385S–389S. 6. Aelony Y, King RR, Boutin C. Thoracoscopic talc poudrage in malignant pleural effusions: effective pleurodesis despite low pleural pH. Chest 1998;113:1007–1012. 7. Cheng D, Chan YM, Ng TY, Cheung AN, Ngan HY, Wong LC. Mitomycin chemotherapeutic pleurodesis to palliate malignant pleural effusions secondary to gynecological cancer. Acta Obstet Gynecol Scand 1999;78:443– 446. 8. Ong KC, Indumathi V, Raghuram J, Ong YY. A comparative study of pleurodesis using talc slurry and bleomycin in the management of malignant pleural effusions. Respirology 2000;5:99 –103. 9. Chella A, Ribechini A, Dini P, Adamo C, Mussi A, Angeletti CA. [Treatment of malignant pleural effusion by percutaneous catheter drainage and chemical pleurodesis.] Minerva Chir 1994;49:1077–1082. 10. Rosso R, Rimoldi R, Salvati F, et al. Intrapleural natural beta interferon in the treatment of malignant pleural effusions. Oncology 1988;45:253–256. 11. Lissoni P, Mandala M, Curigliano G, et al. Progress report on the palliative therapy of 100 patients with neoplastic effusions by intracavitary low-dose interleukin-2. Oncology 2001;60:308 –312. 12. Senyigit A, Bayram H, Babayigit C, Topc¸u F, Balci AE, Satici O. Comparison of the effectiveness of some pleural sclerosing agents used for control of effusions in malignant pleural mesothelioma: a review of 117 cases. Respiration 2000;67:623– 629. 13. Ren S, Terman DS, Bohach G, et al. Intrapleural staphylococcal superantigen induces resolution of malignant pleural effusions and a survival benefit in non-small cell lung cancer. Chest 2004;126:1529 –1539. 14. Uehara T, Yano T, Kuninaka S, Yoshino I, Asoh H, Ichinose Y. The influence of enhanced postoperative inflammation by the intrapleural administration of streptococcal preparation (OK-432) on the prognosis of completely resected non-small-cell lung cancer. J Surg Oncol 2000; 75:51–54. 15. Yoshida K, Sugiura T, Takifuji N, et al. Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously untreated non-small cell lung cancer: JCOG 9515. Lung Cancer 2007;58:362–368. 16. Shimizu T, Takahashi N, Terakado M, Akusawa H, Tsujino I, Horie T. Influence of lymphocytes in malignant pleural effusion on the therapeutic efficacy of intrapleural OK-432 in lung cancer patients. Intern Med 2006;45:715–720. 17. Ishida A, Miyazawa T, Miyazu Y, et al. Intrapleural cisplatin and OK432 therapy for malignant pleural effusion caused by non-small cell lung cancer. Respirology 2006;11:90 –97. 18. Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer 1999;86:1992–1999. 19. Martinez-Moragon E, Aparicio J, Rogado MC, Sanchis J, Sanchis F,

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