Comparison of intrapleural OK-432 and cisplatin for malignant pleural effusion in lung cancer patients

Malignant pleural effusion is typical of complications in advanced lung cancer patients, most of whom complain of dyspnea. The standard treatment for symptomatic pleural effusion is intrapleural administration of a chemical agent. In Japan, OK-432, a streptococcal preparation, and cisplatin (CDDP) have been among the most frequently used chemical agents. There have been very few reports on the efficacy of chemical agents for malignant pleural effusion. We compared therapeutic efficacy and toxicity of intrapleural OK-432 with CDDP in a case-control study. The subjects consisted of 32 lung cancer patients with malignant pleural effusion who were admitted to our hospital between January 2000 and June 2004. The therapeutic efficacy was assessed from duration of chest drainage after intrapleural administration, response rate, time to progression of malignant pleural effusion, and survival time. No statistically significant difference was observed for therapeutic efficacy. Although the OK-432-treated group had only grade 1 fever, chest pain, nausea, the CDDP-treated group had a grade 2 increase in creatinine and grade 3 nausea. Intrapleural OK-432 seemed to be better tolerated in the treatment of malignant pleural effusion than intrapleural CDDP.     

Intrapleural chemotherapy--current status and problems in Japan

The efficacy of anti neoplastic agents for chest catheter pleurodesis remains controversial, and little is known regarding the optimal treatment protocol. Of the various anti neoplastic agents, bleomycin and cisplatin are preferred for intrapleural therapy in Japan, and a wide variation among institutions is evident in agent doses and medication methods for pleurodesis. In many reported trials of anti neoplastic pleurodesis, problems exist such as disease heterogeneity, small sample size and differences in response criteria, and randomized control trials (RCTs) are needed to establish evidence. The JCOG 9515 trial randomly assigned patients to either the bleomycin (BLM) arm, the OK-432 arm, or the cisplatin+etoposide (PE) arm. Among them, OK-432 was demonstrated to be more effective than BLM or PE in terms of pleural progression-free survival. Intrapleural combination therapy (chemotherapy plus biological response modifiers) appeared to be superior to either alone, and further randomized studies are warranted.     

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.     

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.     

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。     

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

To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3-4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK-432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate.     

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.      

Administration of docetaxel in cases of recurrent breast carcinoma with malignant pleural effusion controlled by intrapleural administration of OK-432

Docetaxel is an anti-tumor agent which promotes the congregation and stabilization of microtubules, there by preventing cell division. It is reported to have anti-tumor activity against breast or non-small cell lung carcinomas which have been resistant to other anti-tumor agents. On the other hand, it causes peripheral edema and effusion in the pleural or peritoneal cavities. Thus, pleural or peritoneal effusions, which require drainage have been considered to be contraindications for the administration of docetaxel. OK-432 is an agent which causes adhesion by evoking a local inflammatory reaction. We experienced two cases of recurrent breast carcinoma with malignant pleural effusion. We successfully managed their pleural effusion with the intrapleural administration of OK-432. Thereafter, we safely administered docetaxel, and obtained good outcomes. The present paper also discussed the synergistic action between these agents.     

Intrapleural palliative treatment of malignant pleural effusions with mitoxantrone versus placebo (pleural tube alone).

From 11/87 until 7/90 103 patients entered a prospective randomized trial on the treatment of malignant pleural effusions (MPE) with intrapleural mitoxantrone versus placebo (pleural tube alone with instillation of isotonic NaCl). Our data suggest no statistically significant difference between the two arms with respect to response and response duration. There is no influence on survival time. The toxicity is moderate, with only fever occurring more often in the mitoxantrone arm. We recommend performance of pleurodesis in patients with MPE first by sufficient drainage with a tube of 16-20 char. Only in instances of failure it is necessary to add sclerosing agents such as tetracycline, etc.     

Optimal therapy of malignant pleural effusions

A randomized phase III trial of bleomycin, tetracycline and talc following chest tube drainage and a meta-analysis of relative benefit of bleomycin and tetracycline as sclerosing agents were performed to determine the optimal approach to malignant pleural effusion (MPE). Fifty patients were randomized to receive bleomycin (n=16), tetracycline (n=19) or talc (n=16) following chest tube drainage. Treatment groups were balanced for pretreatment characteristics. The study was ended prematurely because of the removal of parenteral tetracycline from the market. Overall, 52% of randomized patients had successful control of effusion 30 days after sclerosis. There were no differences between any of the three treatment groups in terms of 30 day control of effusion, overall survival (6 months), resclerosis rate, pain with sclerosis, fever, or duration of hospitalization (6 days). A meta-analysis was performed using the four previously reported trials of tetracycline vs. bleomycin and revealed a 20.6% advantage to the use of bleomycin (95% C.I. 7.9%-33.3%) (p=0.002). This phase III failed to demonstrate a significant difference between the three agents in terms of control of MPE at 30 days, side effects or survival. However, because of small sample size, this study lacks sufficient power to observe potentially clinically important differences between treatment groups. Inclusion of data from four previous trials in a meta-analysis showed that bleomycin may be superior. The median duration of hospitalization and the overall success rate of all three sclerosing agents in this study argue convincingly that new approaches to palliate MPE are needed.     

顺铂联合甘露聚糖肽与联合OK-432胸腔注射治疗恶性胸腔积液的临床分析

[目的]对比观察中心静脉导管胸腔引流并顺铂联合甘露聚糖肽（多抗）或OK-432（沙培林）治疗恶性胸腔积液的临床疗效和毒副反应。[方法]99例恶性胸腔积液病人，随机分为2组：甘露聚糖肽组（A组）53例，OK432组（B组）46例。行中心静脉导管胸腔引流术，A组胸腔注射甘露聚糖肽和顺铂，B组胸腔注射0K432和顺铂。两组均每周重复，连续2～4周。[结果]A组RR43例（81．1％）。B组RR39例（84．8％），两组有效率无统计学差异（P=0．631）。A组有3例（5．7％）病人发热，B组有24例（52．2％）病人发热（P〈0．001）。[结论]中心静脉导管胸腔引流并顺铂联合甘露聚糖肽或OK432治疗恶性胸腔积液均较安全且方便，临床疗效相似，但沙培林组发热的发生率远高于甘露聚糖肽组。     

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.     

Local application of anti-cancer drugs for the treatment of malignant pleural and pericardial effusion

Pleural effusion is a common complication in patients with malignant neoplasm. A randomized controlled study of intrapleural instillation of Adriamycin (control group, 30 patients) and Adriamycin Nocardia rubra cell wall skeleton (N-CWS group, 26 patients) with tube thoracostomy was performed in 55 patients with malignant pleural effusion due to primary lung cancer. The response rates for control of pleural effusion were 73.4% in the N-CWS group and 46.1% in the N-CWS group. These results suggest that intrapleural instillation using a combination of anti-cancer agent and immunopotentiator is an effective treatment for malignant pleurisy. Cardiac tamponade secondary to cancer is a life-threatening complication requiring immediate treatment. Twenty-four patients with malignant pericardial effusion were treated by intrapericardial instillation of anti-cancer drugs, such as Carbazilquinone, Mitomycin-C or ACNU, with pericardial drainage. The range of survival time from the instillation of anti-cancer drug was 3-365 days (average days). In only 4 patients, reaccumulation of pericardial effusion was recognized. There were no serious complications with this procedure. It was considered that local instillation of anti-cancer agents with pericardial drainage was a useful therapeutic modality for malignant pericarditis.     

Two patients of recurrent breast cancer with carcinomatous pleurisy well controlled pleural effusion

We report two patients of recurrent breast cancer with carcinomatous pleurisy well controlled pleural effusion. One patient is a 49-year-old woman. She underwent radical mastectomy for right breast cancer in September 1993. She suffered from multiple liver metastases in June 2000, so CEF therapy contained hepatic arterial infusion chemotherapy and extended right lobectomy of the liver were performed in December 2001. Right pleural effusion was detected in December 2003, then, pleurodesis was carried out with OK-432 after thoracic drainage. After pleurodesis, a weekly paclitaxel therapy was started and she was taking the regimen continuously. Another patient is a 55-year-old woman. She underwent radical mastectomy for left breast cancer in September 1999. Local recurrent lesions on the left chest and left pleural effusion were found in May 2003. After thoracic drainage, infectious pleurisy was complicated, so the drainage tube was removed after the therapy for preventing infection. After pleurodesis, CE therapy followed by peroral chemo-endocrine therapy was performed. Both of the two patients are receiving outpatient treatment without recurrent pleural effusion as of July 2005.     

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.     

胸腔镜下胸膜腔闭锁术治疗恶性胸腔积液的临床评价

为了评价胸腔镜下胸膜腔闭锁术治疗恶性胸腔积液的优势及效果,对48例恶性胸腔积液患者行胸腔镜下胸膜腔闭锁术,所有患者均在全身麻醉双腔气管插管胸腔镜（video-assisted thoracoscopic surgery,VATS）下进行,术中吸净胸腔积液,分离纤维粘连,5例行部分胸膜剥脱,同时行多处胸膜活检。然后用连接多侧孔尿管的喷球,将5～10g无菌医用滑石粉均匀喷洒到脏、壁层胸膜表面,达到胸膜腔闭锁,术中放置带多侧孔的引流管,术后引流3～6d。48例患者无围手术期死亡。术后2例（4.17%）发生持续漏气,均经持续负压吸引后治愈。随访47例患者（97.92%）,随访时间为3个月。胸膜腔闭锁成功46例（95.83%）;2例失败,其中1例再次行该手术成功。初步研究结果提示,VATS下喷洒滑石粉用于胸膜腔闭锁,安全、可靠,可有效治疗恶性胸腔积液。     

Intracavitary bleomycin and tetracycline in the management of malignant pleural effusions: a randomized study

Both bleomycin and tetracycline have been suggested as the sclerosing agent of choice in the management of malignant pleural effusions. To determine if one drug is superior to the other in this role, patients with malignant pleural effusions were randomly assigned to receive either bleomycin or tetracycline in the previously evacuated pleural space through a thoracostomy tube. Following instillation of the assigned agent, the tube was clamped for 8 hours and then reattached to suction. When the chest tube drainage had slowed to less than 40 ml in a 24-hour period or if 7 days had passed, the tube was removed. Pleural sclerosis was attempted 42 times in 34 patients. No statistically significant differences were found between the two treatment groups when prevention of effusion reaccumulation and time to removal of the chest tube (efficiency) were compared. Side effects including pleural pain and fever, occurred with both agents, but were manageable. Since one drug was not clearly superior to the other, and bleomycin is more costly, we suggest that tetracycline rather than bleomycin be used when pleural sclerosis is needed to manage malignant pleural effusions.     

Intrathoracic infusion with a combination of low-dose minocycline, OK-432 and cisplatin for malignant pleural effusion

We investigated the effectiveness and complications of intrathoracic infusion with a combination of cisplatin, OK-432, and minocycline for malignant pleural effusion. All patients were hospitalized with chest tube drainage of pleural effusion until the daily drainage volume was less than 100 ml. Twenty-five mg of minocycline, 1 to 3 KE of OK-432, and 5 to 10 mg of cisplatin were instilled into the pleural space. The administration was repeated until drainage effusion disappeared. Therapeutic effect was evaluated according to the following criteria: (1) excellent, no fluid reaccumulation for at least 4 weeks as determined by chest radiogram and clinical evaluation; (2) effective, fluid reaccumulation less than 50% of original effusion with no need of thoracentesis for symptomatic relief within 4 weeks after treatment; and (3) failure, reaccumulation of more than 50% of the original effusion requiring thoracentesis to relieve symptoms within 4 weeks of treatment. Twelve patients with malignant effusion received the combination treatment; 11 patients had primary lung cancer and one had metastatic lung tumor from cancer of the rectum. In all cases, the histology or cytology revealed adenocarcinoma. Eleven of the 12 patients had an excellent response with relief of clinical symptoms. The remaining case failed to show any improvement. Complications such as local pain, fever, nausea, and vomiting were mild and transient. We conclude that combination administration of low-dose minocycline, OK-432, and cisplatin into the thoracic cavity for malignant effusion is an effective alternative treatment with the potential for improvement of the general condition and reduced morbidity.     

双路径化疗治疗老年人恶性胸腔积液40例临床分析

目的探讨胸膜腔（以下简称胸腔）置管引流并双路径化疗治疗老年恶性胸膜腔积液（以下简称胸腔积液）的疗效及不良反应。方法40例肺癌并恶性胸腔积液的老年病人,Ps评分1-2分,行胸腔置管引流术后,胸腔内灌注博莱霉素（BLM）每次60mg,lL-2每次200万IU,1次／wk,同步吉西他滨单药化疗（800—1000mg／m^2,ivdrip,d1,d8,d15,每4wk重复）,观察不良反应,2周期后评价疗效。结果全组有效率为85．0％（34／40）,CR10例（25％）,PR24例（60％）,NR6例（15％）,中位生存期10mo,主要不良反应为I—II°血小板减少及皮疹。结论胸腔置管引流并双路径化疗治疗老年恶性胸腔积液疗效好,不良反应较轻,是一种可行有效的综合治疗方法。     

Multidisciplinary management of malignant pleural effusion

Approximately 50% of patients with metastatic disease develop a malignant pleural effusion (MPE). Prompt clinical evaluation and treatment to achieve successful palliation are the main goals of management of MPE. Optimal treatment is still controversial and there is no universal standard approach. Management options include observation, thoracentesis, indwelling pleural catheter (IPC) or chest tube placement, pleurodesis, and surgical pleurectomy. The treatment for each patient should be based on symptoms, general condition, and life expectancy.