Comparison of OK-432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial.

A prospective randomized study to compare the effectiveness of pleurodesis by two new sclerosing agents: OK-432 and mitomycin C were conducted in 53 patients with malignant pleural effusion caused by lung cancer. None of the patients received concomitant systemic chemotherapy or radiation therapy during the study. After complete drainage of pleural fluid, the patients were allocated randomly to receive 10 Klinische Einheit units of OK-432 or 8 mg of mitomycin C by intrapleural injection at weekly intervals. The treatment was terminated if the pleural effusion disappeared or the patients had received four consecutive procedures. There were 26 patients who received pleurodesis with OK-432 and 27, with mitomycin C. Patient characteristics in the two treatment groups (age, sex, histologic type, performance status, and prior treatment before pleurodesis) were compatible. These results showed that pleurodesis with OK-432 achieved a higher complete response rate (73%) than that of mitomycin C (41%). The rates of objective treatment response (complete response plus partial response) were comparable in both groups (88% for OK-432 and 67% for mitomycin C). The average number of intrapleural injections needed to achieve complete response was fewer in the OK-432 group (1.9 +/- 0.9) than in mitomycin C group (2.8 +/- 0.9). There was no significant difference in the median survival of the patients who received pleurodesis with OK-432 (5.8 months) or mitomycin C (5.1 months). However, the effusion-free period in the OK-432 group was significantly longer than that in the mitomycin C group (7.0 months versus 1.5 months). Patients who underwent OK-432 pleurodesis had a higher complication rate (80%) than did those in the mitomycin C group (30%). Transient febrile reaction was the most common reaction encountered. The immunologic study in OK-432 group showed an increase in peripheral leukocyte count and decrease in the OKT4/OKT8 ratio. The mitomycin C group had a mild reduction in peripheral blood leukocyte count and no significant change in the OKT4/OKT8 ratio. It was concluded that pleurodesis with OK-432 is an effective alternative treatment for malignant effusion in patients with lung cancer.     

Vandetanib and Indwelling Pleural Catheter for Non–Small-Cell Lung Cancer With Recurrent Malignant Pleural Effusion

Introduction/BackgroundNon–small-cell lung cancer patients with malignant pleural effusion have a poor overall median survival (4.3 months). VEGF is a key regulator of pleural effusion production. It is unknown if pharmacological inhibition of VEGF signaling modifies the disease course of non–small-cell lung cancer patients with recurrent malignant pleural effusion. We report the final results of a single-arm phase II clinical trial of the VEGF receptor inhibitor, vandetanib, combined with intrapleural catheter placement in patients with non–small-cell lung cancer and recurrent malignant pleural effusion, to determine whether vandetanib reduces time to pleurodesis.Patients and MethodsNon–small-cell lung cancer patients with proven metastatic disease to the pleural space using pleural fluid cytology or pleural biopsy who required intrapleural catheter placement were eligible for enrollment. On the same day of the intrapleural catheter insertion, the patients were started on a daily oral dose of 300 mg vandetanib, for a maximum of 10 weeks. The primary end point was time to pleurodesis, with response rate as the secondary end point. Exploratory analyses included measurement of pleural fluid cytokines and angiogenic factors before and during therapy.ResultsTwenty eligible patients were included in the trial. Eleven patients completed 10 weeks of treatment. Median time to pleurodesis was 35 days (95% confidence interval, 15-not applicable). Median time to pleurodesis in the historical cohort was 63 days (95% confidence interval, 45-86) when adjusted for Eastern Cooperative Oncology Group performance status ≤ 2.ConclusionVandetanib therapy was well tolerated; however, it did not significantly reduce time to pleurodesis.     

Ultrasound-guided small-bore Elecath tube insertion for the rapid sclerotherapy of malignant pleural effusion

BACKGROUND: Traditional pleurodesis for malignant pleural effusion is performed by large-bore chest tube insertion with the instillation of sclerosing agents after the compressed lung re-expansion and pleural fluid drainage of 100-150 ml/day. This study was carried out to evaluate the possibility of rapid sclerotherapy for malignant pleural effusions by insertion of a small-bore Elecath tube (12-French) under ultrasound guidance and intrapleural injection of bleomycin 60 IU. METHODS: Twenty-six patients, with 28 cytopathologically proven malignant pleural effusions (two patients had bilateral pleural effusions) and receiving the insertion of the Elecath tube for drainage, were included in our series. This rapid and short-term sclerosing method was performed and completed by intrapleural injection of bleomycin when the pleural effusion had been clearly drained by the small-bore Elecath tube and the compressed lung had fully re-expanded on follow-up chest radiographs. RESULTS: Twenty patients with 22 pleural effusions underwent the intrapleural injection of bleomycin, with the results of pleurodesis being complete response 41% (9/22), partial response 36% (8/22) and failure 23% (5/22). Interestingly, among the 17 successful procedures of pleurodesis (complete response and partial response), 71% (12) procedures could be completed within 2 days (seven within one day and five within 2 days). The remaining unsuccessful procedures carried out on six patients without the injection of bleomycin were due to a non-re-expanded lung (n = 3) and inadequate drainage (n = 3); of these, four patients also received the large-bore chest tube insertion after the removal of the Elecath tube, but the compressed lung still could not re-expand. The complications of the bleomycin injection were fever [77% (17/22)], vomiting [14% (3/22)] and hiccup [5% (1/22)]. CONCLUSION: The method of rapid sclerotherapy for malignant pleural effusions by small-bore Elecath tube is promising, with a success rate achieving 77%, usually within 2 days.      

Epidermal growth factor receptor in breast cancer: Correlation of quantitative immunocytochemical assays to prognostic factors

Summary Sixty-seven breast cancer patients with cytologically-confirmed malignant pleural effusion, who required intrapleural treatment, were analyzed retrospectively. The patients received their first thoracentesis between 1980 and 1990. Among them, 29 patients received intrapleural administration of OK-432, a streptococcal preparation, followed by the transfer of autologous pleural effusion lymphocytes cultured with interleukin-2. Other intrapleural treatments consisted of OK-432 alone (12 patients), chemotherapeutic agents alone (n = 9), a combination of OK-432 and chemotherapy (n = 16), or others (n = 1). Twenty-six of the 29 patients given OK-432 plus cultured effusion lymphocytes responded, while only 15 of the 38 patients who received other treatments did (p < 0.01). Median survival time and 5-year survival rate of patients who received OK-432 and cultured lymphocytes was 12 months and 36%, while those of the patients who received other treatments was 3 months and 0%, a significant (p< 0.001) difference in survival. Multivariate analysis using Cox's proportional hazard model revealed that the treatment (adoptive immunotherapy) was the most significant (p < 0.005) factor to prolong the survival of the patients among several prognostic factors. Thus, OK-432 and adoptive immunotherapy is a promising therapy that should be further evaluated in a prospective study.     

Vincristine (Vinca-alkaloid) as a sclerosing agent for malignant pleural effusions

Vincristine, extracted from Vinca rosea Linn., is an effective antineoplastic chemotherapeutic drug used in oncology practice. This drug has never been used as a sclerosing agent for the treatment of malignant pleural effusion for reasons unknown. A study was conducted to examine the use of Vinca-Alkaloid as a sclerosing agent (pleurodesis) for the palliative treatment of malignant pleural effusions. The study included 15 patients, all diagnosed to have cytology-proven malignant pleural effusions. Intercostal tube drainage followed by chemical sclerotherapy with 2 mg vincristine was performed on all patients and a high success rate was noted. Twelve procedures out of 15 (12/15) achieved complete resolution of pleural fluid with a success rate of 80%. In two procedures the pleural effusion was reduced and then recurred but did not require re-aspiration. One procedure failed and repeated pleural aspiration was required. In this study, with adequate pleural drainage and the proper technique, vincristine was found to be an effective sclerosing agent for malignant pleural effusion. Further randomized trials are necessary in order to establish the role of this drug.     

微导管引流顺铂联合白介素-Ⅱ治疗恶性胸腔积液疗效观察

目的探讨微导管引流联合白介素-Ⅱ胸腔内注入治疗恶性胸腔积液的疗效。方法选择恶性胸腔积液患者60例,均用微导管穿刺引流胸水,随机分为两组给药,A组30例,单用顺铂注入胸膜腔中;B组30例,首先用顺铂注入,第2天用白介素-Ⅱ200万u注入。结果 A组总有效率70.0%,B组总有效率86.7%,B组疗效优于A组。两组副作用对比差异无统计学意义。Kanofsky评分两组用药后均明显上升。结论联合用药的疗效明显优于单药使用,而微导管的应用,更利于治疗的进行。     

Long-term effect and tolerance of talc slurry for control of malignant pleural effusions

Drainage of malignant pleural effusions (MPE) by thoracocenthesis and subsequent pleurodesis is an established means of symptomatic relief in terminally-ill patients, but the optimal therapy remains unclear. Among many sclerosing agent, talc is the most widely used, but its intrapleural administration and dosage have not been clearly determined. To assess the efficacy of using talc slurry with high dose (8 g) as a sclerosing agent instilled into the pleural space at the patient bedside, we carried out a study in 31 patients suffering from symptomatic MPE, followed until death or up to 1 year with radiographs. Patients were evaluated for immediate tolerance (31 patients), and for efficacy and long-term tolerance (27 patients) of the talc therapy. We have shown, that pleurodesis was satisfactory in 22/27 patients (81.4%). This result appeared comparable with other series. Moreover, we observed a long-lasting efficacy: within 6 months and within 12 months after talc instillations, 20/20 patients and 9/9 patients respectively were symphysed with efficacy. Complications related to talc (8 g) were rare and moderate (pain, fever). Taking into account some technical aspects of talc instillation for good performance of the therapy, we recommend this method as the optimal route of administration.     

新鱼腥草素钠联合顺铂胸腔灌注治疗恶性胸水的临床观察

目的研究新鱼腥草素钠注射液联合顺铂治疗恶性胸腔积液的临床效果。方法将50例恶性胸水患者随机分为治疗组和对照组,治疗组25例应用新鱼腥草素钠注射液加顺铂胸腔灌注,对照组25例单纯应用顺铂治疗,观察治疗前后胸水的变化和副反应。结果治疗组胸水控制有效率(CR PR)为96.0%,对照组为56.0%,两组相比差异有显著性(P<0.01)。治疗组副反应为轻度发热、胸痛,对照组为骨髓抑制、胃肠道反应及胸痛。结论新鱼腥草素钠注射液联合顺铂胸腔灌注能有效地控制恶性胸腔积液,毒副反应小,疗效肯定。     

Pleuritis carcinomatosa

The most used standard therapy for malignant pleural effusion(MPE)is tube thoracostomy drainage, except in cases where there are few pleural effusions or no symptoms. It has been reported that instilling an intrapleural agent is necessary for producing pleurodesis after tube thoracostomy drainage. To date, numerous chemical agents for the treatment of MPE have been studied. These include antibiotics, antineoplastic agents, biological response modifiers and others, that showed various degrees of chemical sclerosis. It was entered on a randomized comparison of tetracycline and bleomycin for treatment of MPE. The rate and time to recurrence were both significantly greater with bleomycin. In comparison, Talc was superior to bleomycin for control of MPE. Therefore, thoracoscopic pleurodesis with talc is now considered to be the gold standard treatment for MPE. However, talc has not been commercially available in Japan. We sought to evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin, OK-432 or cisplatin plus etoposide(PE), for the management of malignant pleural effusion in previously untreated non-small cell lung cancer. The primary endpoint, pleural progression-free survival did not differ significantly between groups. Intrapleural treatment using OK-432 in the management of MPE was selected because it had the highest 4-week pleural progression-free survival rate and toxicity was tolerable. At present, OK- 432 is the standard agent used in Japan.     

力尔凡联合顺铂胸腔灌注治疗恶性胸水的临床观察

目的研究力尔凡联合顺铂治疗恶性胸腔积液的临床效果.方法将48例恶性胸水患者随机分为治疗组和对照组,治疗组25例应用力尔凡加顺铂胸腔灌注,对照组23例单纯应用顺铂治疗,观察治疗前后胸水的变化和副作用.结果治疗组控制胸水的有效率(CR PR)为96.0%,对照组为56.5%,两组相比差异有显著性(P＜0.01).治疗组副作用为轻度发热、胸痛,对照组为骨髓抑制、胃肠道反应及胸痛.结论力尔凡联合顺铂胸腔灌注能有效地控制恶性胸腔积液,毒副作用小,疗效肯定.     

Management of malignant pleural effusion

Malignant pleural effusion (MPE) often presents in patients with cancer at an advanced stage and thus carries a poor prognosis. This review updates the current knowledge on the management of MPE, focusing on recent literature about the efficacy and safety of the most common methods, including pleurodesis by either thoracoscopy with talc insufflation or thoracostomy with talc slurry, use of an indwelling pleural catheter, and intrapleural chemotherapy. Talc remains the agent of choice in pleurodesis, although the use of alternative agents continues to be explored. The choice of procedure to achieve pleurodesis depends on careful patient selection based on predictive factors and individual characteristics. Talc pleurodesis is relatively well tolerated and safe, as is an indwelling pleural catheter, in an appropriate patient population. Because MPE is a common problem in cancer patients, future research with more randomized, prospective designs and innovative interventions is needed.     

A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions

BACKGROUND: The purpose of this study was to compare the effectiveness and safety of a chronic indwelling pleural catheter with doxycycline pleurodesis via tube thoracostomy in the treatment of patients with recurrent symptomatic malignant pleural effusions (MPE). METHODS: In this multi-institutional study conducted between March 1994 and February 1997, 144 patients (61 men and 83 women) were randomized in a 2:1 distribution to either an indwelling pleural catheter or doxycycline pleurodesis. Patients receiving the indwelling catheter drained their effusions via vacuum bottles every other day or as needed for relief of dyspnea. RESULTS: The median hospitalization time was 1.0 day for the catheter group and 6.5 days for the doxycycline group. The degree of symptomatic improvement in dyspnea and the quality of life was comparable in each group. Six of 28 patients who received doxycycline (21%) had a late recurrence of pleural effusion, whereas 12 of 91 patients who had an indwelling catheter (13%) had a late recurrence of their effusions or a blockage of their catheter after the initially successful treatment (P = 0.446). Of the 91 patients sent home with the pleural catheter, 42 (46%) achieved spontaneous pleurodesis at a median of 26.5 days. CONCLUSIONS: A chronic indwelling pleural catheter is an effective treatment for the management of patients with symptomatic, recurrent, malignant pleural effusions. When compared with doxycycline pleurodesis via tube thoracostomy, the pleural catheter requires a shorter hospitalization and can be placed and managed on an outpatient basis.     

Blockage of vascular endothelial growth factor (VEGF) reduces experimental pleurodesis

Background and objective

Chemical pleurodesis controls recurrent malignant pleural effusion. The mechanism that determines pleural symphysis involves the action of vascular endothelial growth factor (VEGF). We assessed the influence of the anti-VEGF antibody (bevacizumab) on pleurodesis induced by talc or silver nitrate and analyzed the temporal development of pleural angiogenesis.

Methods

Sixty New Zealand rabbits received intrapleural injection (2 mL) of talc (400 mg/kg) or 0.5% silver nitrate. In each group, half of the animals received an intravenous injection of bevacizumab 30 min before the sclerosing agent. Five animals from each group were euthanized 7, 14, or 28 days after the procedure. Adhesions and inflammation (scores: 0-4), thickness (μm), vascular density (vessels/field), and collagen fibers (μm²) were evaluated in the visceral pleura.

Results

Antibody anti-VEGF interferes in pleurodesis induced by talc or silver nitrate. Pleural inflammation was discreet with no difference between the groups, regardless the anti-VEGF treatment. Concerning the vascular density of the visceral pleura, a smaller number of neoformed vessels was noted in the animals that received bevacizumab. In the animals receiving silver nitrate, the decrement in adhesions and vascular density was associated with reduced thick and thin collagen fibers, resulting in less pleural thickness.

Conclusion

The anti-VEGF antibody inhibits adhesions between pleural layers. Despite being an experimental study in animals with normal pleura, the results call attention to a likely lack of success in pleurodesis when VEGF blockers are used.     

Prospective randomized trial of intrapleural bleomycin versus interferon alfa-2b via ultrasound-guided small-bore chest tube in the palliative treatment of malignant pleural effusions.

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.     

Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial

Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.     

局部灌注沙培林和羟基喜树碱治疗恶性胸腔积液

[目的]观察沙培林(0K-432)和羟基喜树碱(HCPT)治疗恶性胸腔积液的近期临床疗效。[方法]对62例恶性胸腔积液患者采用胸腔置入贝朗可分裂中心静脉管持续引流，胸腔积液排放完后，给予沙培林5KE胸腔内注入，dl，HCPT30mg胸腔内注入，d2，每周2次，观察临床疗效与不良反应。[结果]沙培林与HCPT联合治疗恶性胸腔积液总有效率为88．7％，主要不良反应为发热和骨髓抑制。[结论]胸穿置管引流局部灌注沙培林和羟基喜树碱治疗恶性胸积液有较好的近期临床疗效，毒副反应可以耐受。     

肿瘤局部切除联合胸腔热灌注治疗周围型肺癌伴恶性胸腔积液

目的：观察肿瘤局部切除联合胸腔热灌注治疗肺癌伴恶性胸腔积液的临床疗效。方法：36例肺癌伴恶性胸腔积液患者,开胸或在电视胸腔镜下楔形切除肺部肿瘤,并以43℃热蒸馏水循环灌注胸腔90—120min,观察其临床疗效。结果：治疗后恶性胸腔积液控制有效率达100％,所有患者未见胸腔积液复发,患者生活质量明显提高,全组中位存活期达13．56个月。结论：肿瘤局部切除联合胸腔热灌注治疗能有效控制恶性胸腔积液,改善患者生活质量,延长生存时间。     

恩度联合奈达铂胸腔内灌注治疗恶性胸腔积液疗效观察

目的探讨恩度联合奈达铂胸腔内灌注治疗恶性胸腔积液的有效性和安全性。方法将60例恶性胸腔积液患者随机分为试验组和对照组,2组患者均先采用胸腔穿刺置管闭式引流胸腔积液,试验组30例采用恩度（45mg）联合奈达铂（40mg）进行胸腔内灌注,而对照组30例仅采用奈达铂（40mg）进行胸腔内灌注,观察2组的疗效和毒副反应。结果试验组有效率为76．67％,优于对照组的36．67％,差异有统计学意义（P〈0．05）;2组主要毒副反应发生率比较差异无统计学意义（P均〉0．05）;试验组生活质量改善率为73．33％,高于对照组的43．33％,差异有统计学意义（P〈0．05）。结论恩度联合奈达铂胸腔内灌注治疗恶性胸腔积液安全有效。     

Management of malignant pleural effusion by multimodality treatment including the use of paclitaxel administered by 24-hour intrathoracic infusion for patients with carcinomatous pleuritis

For successful intrapleural chemotherapy, intrapleural drug activity should be maintained for as long as possible. This interim report presents the results of treatment with paclitaxel administered by 24-hour intrathoracic infusion as an adjunct to selective surgical management and/or systemic chemotherapy for controlling malignant pleural effusion. Thirteen patients with carcinomatous pleuritis were enrolled in the study between October 2001 and September 2004. The sites of primary disease were the lung in 12 patients and the breast in one patient. Paclitaxel (120 mg/m2) was administered by 24-hour intrathoracic infusion. Seven patients underwent elective surgical treatment and 11 patients received adjuvant systemic chemotherapy. Mild toxicity occurred in 7 cases, and chest pain and neutropenia were dominant. During a median follow-up period of 9 months (range, 2-33 months), malignant effusion was controlled successfully in 11 patients (84.6%). The multimodality treatment, including the use of paclitaxel, in this manner merits further investigation for possible intervention for malignant pleural effusion originating in lung and breast neoplasms.     

肿瘤局部切除联合胸腔热灌注治疗周围型肺癌伴恶性胸腔积液

目的:观察肿瘤局部切除联合胸腔热灌注治疗肺癌伴恶性胸腔积液的临床疗效.方法:36例肺癌伴恶性胸腔积液患者,开胸或在电视胸腔镜下楔形切除肺部肿瘤,并以43℃热蒸馏水循环灌注胸腔90-120min,观察其临床疗效.结果:治疗后恶性胸腔积液控制有效率达100%,所有患者未见胸腔积液复发,患者生活质量明显提高,全组中位存活期达13.56个月.结论:肿瘤局部切除联合胸腔热灌注治疗能有效控制恶性胸腔积液,改善患者生活质量,延长生存时间.