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.      

An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin

Fifty-four consecutive patients with malignant effusions either pleural or peritoneal were treated by a simple aspiration followed by the administration of bleomycin to prevent a recurrence. All patients were followed up until reaccumulation of the effusion or death, with assessments being made of the patient's response at 30 days, 60 days, 90 days, 6 months, 1 year and then annually. There were 42 evaluable patients at 30 days, when the overall response rate for pleural effusions was 80.5% (21/26) and 62.5% (10/16) for peritoneal effusions. Patients who developed an effusion from primary breast neoplasms responded better than other groups, with an overall rate of 81% and 80% for pleural and peritoneal effusions respectively. Thirty percent (13) of the patients whose effusions was controlled by bleomycin required a further aspiration due to a recurrent effusions 9% (4) within the first 90 days and the remainder 21% (9) between 3 and 45 months after initial treatment. Altogether 19% (8/42) of the evaluable patients were effusion free at 1 year and 12% (5/42) clear at 3 years, but only two patients were still alive at four years. Side effects were minimal as 92% (50/54) patients treated experienced no adverse effects and there was no evidence of myelosuppression. The dose of bleomycin instilled varied between 60 mg and 180 mg, with 60 mg being given to 58% of patients and 90 mg to 30%, but there was no evidence to suggest that doses higher than 60 mg were more effective. The author concludes that the instillation of bleomycin following the simple aspiration of a malignant effusion is a safe, effective treatment which can benefit patients with this distressing complication of their malignant disease.     

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.     

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.     

Pharmacokinetics of intrapleural versus intravenous etoposide (VP 16) and teniposide (VM 26) in patients with malignant pleural effusion

The pharmacokinetics of etoposide (VP 16) and teniposide (VM 26) were studied after intrapleural administration to 3 patients with lung cancer and malignant pleural effusion. Comparison with the kinetic behavior of intravenously infused VP 16 and VM 26 in the same patients suggests that intrapleural drug delivery achieves higher and longer-lasting pleural concentrations, thus providing a theoretical basis for the palliative treatment of malignant pleural effusions. Although no systemic toxicity was observed after intrapleural administration of either drug, 1 of the 3 patients developed a transient asymptomatic hemorrhagic pleurisy during the first 2 days after the drug, alerting to the possible local toxicity of such treatment.     

自体不成熟树突状细胞胸腔内注射治疗化疗耐药的肿瘤患者恶性胸腔积液

目的:观察体外扩增的不成熟树突状细胞(dendritic cells,DC)胸腔内注射对恶性胸腔积液的疗效和安全性。方法:从6例对化疗耐药的恶性胸腔积液患者采集外周血单个核细胞,体外细胞因子诱导培养获得不成熟DC,每4周患者胸腔内注射DC(5~10)×107个,连续3次为一疗程,观察治疗后患者胸腔积液的变化及治疗的不良反应,流式细胞仪检测胸水中T细胞、NK细胞亚群。结果:总体疗效为:CR 2例,PR 1例,SD 1例,PD 2例,有效率为50%(3/6),获益率(CR+PR+SD)为66.7%。2例CR均为肾癌患者,缓解时间达26周和147周;3例肺癌患者中1例PR、1例SD及1例PD;1例恶性胸膜间皮瘤PD;治疗中无严重不良反应发生。DC治疗后6例患者胸水中的T细胞百分率均较治疗前上升,但差异无统计学意义;NK细胞百分率较治疗前明显上升(P<0.05)。结论:采用无抗原加载的自体不成熟DC胸腔内注射治疗恶性胸腔积液的疗效肯定,可能主要是通过NK细胞介导,是一种安全、有效的治疗方法。     

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.     

短小棒状杆菌菌苗治疗恶性胸腔积液临床观察

[目的]评价短小棒状杆菌菌苗治疗恶性胸腔积液的疗效和毒性。[方法]应用短小棒状杆菌菌苗胸腔内给药治疗46例恶性胸腔积液患者。[结果]有效率76．1％，其中完全缓解率47．8％；毒副反应主要为发热和胸痛，预防性用药后可控制。[结论]短小棒状杆菌菌苗治疗恶性胸腔积液疗效肯定，毒副反应可控制，充分引流、联合全身化疗可提高疗效。     

晚期肺癌癌性胸水的免疫治疗

Ten patients with advanced lung cancer complicated by malignant pleural effusion were treated by intrapleural transfer of autologous LAK cells induced from lymphocytes of malignant effusions in the presence of rIL-2 and by administration of rIL-2 10 days before and after the transfer of LAK cells. The pleural effusions disappeared in 8 patients and significantly reduced in the other two. The number of tumor cells in the pleural effusion was obviously decreased while the number of lymphocytes was significantly increased. No changes were found in 4 responders during 4 months follow-up after treatment. No serious side effects were observed in all these 10 patients. The results indicated that transfer of LAK cells combined with rIL-2 in the treatment of patients with malignant pleural effusion due to advanced lung cancer is effective, safe and feasible.     

Morphological changes in the pleura caused by intracavitary administration of bleomycin]

We administered bleomycin to the intrapleural cavity of hamsters and observed acute and chronic histological changes of visceral pleura using light and electron microscopies. At 7 days after bleomycin challenge, we could find out the pleural thickening with infiltration of inflammatory cells, and then formation of pleural fibrosis at 28 days. However, in our study there was no abnormal findings of the lung parenchyma in morphology and intraalveolar cells, and lung distensibility. The dose (10-20 units/kg body weight) used in the study did not cause the abnormal changes in the parenchyma, although pleural thickening occurred. We suggest that intracavitary bleomycin administration is safely used for the treatment of malignant pleural effusion.     

Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer

Intrapleural instillations of recombinant interleukin 2 (RIL-2) were performed in 11 patients with malignant pleurisy due to lung cancer. Kinetic studies on RIL-2 concentration in the pleural effusion and serum revealed relatively long-term maintenance of detectable levels of RIL-2 (over 24 h in the pleural effusion and over 8 h in the serum). Clinically, pleural effusions and cancer cells in the effusions disappeared in 9 of the 11 patients 4 to 10 days after the start of the treatment. Lymphokine-activated killer cells were induced in the effusions of responders who exhibited the disappearance of pleural effusion and cancer cells from the effusion, but not in those of the nonresponders. This induction of lymphokine-activated killer cells may result in the disappearance of cancer cells and pleural effusions. Cytological examination of pleural effusions revealed increases of lymphoblasts, immunoblastic large lymphocytes, and eosinophiles in number and proportion in the responder, although such a phenomenon could not be observed in the nonresponders. Main and frequent side effects of intrapleural instillations of RIL-2 were fever up to 39 degrees C, transient increase of pleural effusion, and eosinophilia. No serious side effect was encountered in our experience.     

Intrapleural administration of CDDP against malignant pleural effusions in breast cancer

Malignant pleural effusion in the patients with breast cancer commonly occurs, and is a life-threatening factor. The present paper shows the usefulness of intrapleural administration of CDDP in six cases. A decrease of pleural effusions was observed in all cases. Treatment was effective in two cases of CR and four cases of PR. A median survival from initiation of intrapleural therapy is 17 months (range 2-47 months). This procedure produced distinctly fewer side effects than intravenous administration. The results of this trials suggest that CDDP should be considered as an active agent in the treatment of malignant pleural effusion in the patients with breast cancer.     

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.     

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.     

高聚金葡素与顺铂治疗恶性胸腔积液的疗效观察

 目的　观察高聚金葡素对晚期肺癌合并恶性胸腔积液的疗效。方法　32例设为对照组,常规全身行EP方案化疗并顺铂胸腔内注射;观察组32例 , 在作上述常规治疗的同时,加用肌注和胸腔内注入高聚金葡素。结果　观察 组胸水吸收的有效率达71.9%,karnofsky评分上升率为78.1%均优于对照组的43.8%和40 .6%(P<0.01),而白细胞减少和胃肠道反应的发生率均比对照组低(P<0.01)。结论　在全身和胸腔内应用抗癌药治疗晚期肺癌合并恶性胸腔积液的基础 上加用高聚金葡素可提高胸水吸收的有效率,改善生活质量,减少化疗毒副作用。     

Pharmacokinetics of intrapleural cisplatin for the treatment of malignant pleural effusions

We determined the toxicity and pharmacokinetics of high-dose intrapleural cisplatin (CDDP) as a treatment of malignant pleural effusions (MPE). Fourteen patients with MPE were enrolled in this study. After complete drainage of the fluid, a catheter was inserted into the pleural cavity during a thoracoscopy. CDDP (300 mg) was administered via the catheter in a 6-h infusion. Peak levels, the areas under the concentration curve (AUC), and drug half-lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 6, and 24 h as well as 4, 14, and 21 days after intrapleural administration. The dosage of CDDP ranged from 153 to 203 mg/m2. The time interval between infusion was prolonged until a maximum of 109 days. Only 7/40 infusions were associated with adverse effects in 4 patients (18%). Residual concentrations in pleural fluid (0.66+/-0.07 microgram /ml) were three-fold higher than in plasma (0.13+/-0.07 microgram/ml). In pleural fluid, maximal concentration (Cmax) varied from 19 to 900 microgram/ml and in plasma from 0.34 to 3.65 microgram/ml. AUC in plasma during the three courses was 112+/-49 microgram/ml/d. The T1/2 was 31+/-33 days higher than that previously reported after intravenous administration (8-15 days). Although intrapleural CDDP has the potential advantage of treating the underlying malignancy in addition to controlling the malignant effusion with a good tolerance, it cannot be recommended for the standard control of malignant pleural effusion. Indeed we observed a great variability of intrapleural CDDP concentration depending on the extent of pleural invasion and plasma diffusion. Further studies are needed to determine the value of high-dose intrapleural CDDP for the treatment of MPE.     

Intrapleural or Intraperitoneal Lobaplatin for Treatment of Patients with Malignant Pleural Effusion or Ascites

Aims: To explore efficacy and side effects of intrapleural or intraperitoneal lobaplatin for treating patientswith malignant pleural or peritoneal effusions. Methods: Patients in Jiangsu Cancer Hospital and ResearchInstitute with cytologically confirmed solid tumors complicated with malignant pleural effusion or ascites wereenrolled into this study. Lobaplatin (20-30 mg/m2) was intrapleurally or intraperitoneally infused for patientswith malignant pleural effusion or ascites. Results: From 2012 to 2013, intrapleural or intraperitonea lobaplatinwas administered for patients with colorectal or uterus cancer who were previous treated for malignant pleuraleffusion or ascites. Partial response was achieved for them. Main side effects were nausea/vomiting, and bonemarrow suppression. No treatment related deaths occurred. Conclusion: Intrapleural or intraperitoneal infusionof lobaplatin is a safe treatment for patients with malignant pleural effusion or ascites, and the treatment efficacyis encouraging.     

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.     

An analysis of cytokine status in the serum and effusions of patients with tuberculous and lung cancer

The present study was designed to ascertain whether or not the pleural effusion and serum cytokine levels (granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-10 [IL-10], and interferon-gamma [IFN gamma]) in lung cancer patients differ from tuberculous (TB) pleural effusion, in which a strong cellular immune reaction is found; and, whether cytokine levels are a prognostic factor in lung cancer patients with malignant effusion. A total of 202 lung cancer patients with malignant pleural effusion and 26 patients with TB pleural effusion were studied consecutively between 1995 and 1998. Serum and effusion cytokine levels were analyzed with ELISA assays. The results showed that pleural effusion GM-CSF and IL-10 levels were significantly higher than serum levels in both cancer and TB patients. Pleural effusion IFN gamma levels were significantly higher than serum levels in TB patients. IFN gamma levels in both pleural effusion and serum were significantly higher in TB patients than in those with cancer. No significant difference was found, between TB and cancer patients, in the serum or pleural effusion levels of either IL-10 or GM-CSF. The ratio of pleural effusion IFN gamma to serum IFN gamma, effusion IFN gamma to effusion IL-10, and effusion IL-10 to serum IL-10, were all significantly higher in TB than in cancer patients, suggesting a higher cellular activity and T-helper 1 (Th1) reaction in TB pleural effusion than in malignant effusions, which were predominantly Th2 type. Survival analysis showed no significant difference in lung cancer patients with different levels of these cytokines. It was concluded that lung cancer patients with malignant pleural effusion had poorer immune profiles than those with TB pleurisy, both locally and systemically; and the cytokine profiles were not prognostic factors for lung cancer patients with malignant pleural effusion.     

博莱霉素联合白介素2治疗肺癌恶性胸腔积液疗效观察

目的观察博莱霉素联合白介素2(IL-2)治疗肺癌恶性胸腔积液的疗效和不良反应。方法将经病理或细胞学确诊的68例肺癌恶性胸腔积液患者随机分为两组,A组38例,胸腔内注入博莱霉素60 mg+IL-2 100万单位+生理盐水50 ml+地塞米松5 mg。B组30例,注入顺铂60 mg+生理盐水50 ml+地塞米松5 mg。每周1次,连续治疗2～3周后观察疗效、生活质量和不良反应。结果 A组的总有效率为84.0%,B组为53.0%(P<0.05);A组的病变进展率明显低于B组(P<0.05);A组Karnofsky评分≥70分的患者显著高于B组(P<0.05),而A组Karnofsky<50分的患者显著低于B组(P<0.05)。不良反应方面,两组患者在恶心、呕吐及白细胞减低的发生率上,A组明显低于B组(P<0.05)。结论博莱霉素联合IL-2胸腔注入治疗肺癌恶性胸腔积液的疗效确切且不良反应轻微,值得临床推广。