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.     

A case of pericardial tamponade caused by recurrent breast cancer treated with intrapericardial and intrapleural infusion of cisplatin (CDDP)

Breast cancer rarely metastasizes to the pericardial cavity to cause cardiac tamponade. We have recently experienced a case of pericardial tamponade due to recurrent breast cancer. A 41-year-old woman who underwent modified radical mastectomy for a right breast cancer (T(1)N(3)M(0), Stage IIIA) 8 years and 8 months ago, was admitted for dyspnea and cough. Chest X-ray and CT scan revealed cardiomegaly and right pleural effusion, and cardiac echogram showed marked retention of pericardial effusion. A diagnosis of cardiac tamponade was made, and pericardiocentesis and thoracentesis were carried out immediately. Based on cytodiagnosis of pericardial and pleural effusion, the diagnosis was pericardial and intrapleural metastases of the breast cancer. Dyspnea was improved by pericardiocentesis and thocacentesis. Both intrapericardiac and intrathoracic instillation of CDDP prevented reaccumulation of pericardial and pleural effusion. After local chemotherapy with CDDP, systemic chemotherapy of CPT-11 was started. Thereafter the patient was discharged from the hospital and recovered her daily activities. This case indicates that intrapericardiac application of CDDP was effective for carcinomatous cardiac tamponade without serious side effects.     

A case of breast cancer with pleural metastasis responding to administration of intrapleural adriamycin and systemic chemotherapy with FEMP

A 51-year-old woman with breast cancer metastatic to the pleura was treated with intrapleural instillation of adriamycin after thoracentesis, and systemic administration of FEMP, with complete response for more than 11 months. She underwent radical mastectomy and bilateral oophorectomy for advanced breast cancer, and 18 months later presented radiological evidence of pleural fluid contralateral to the affected breast. Initially, thoracentesis for symptomatic relief was done with a positive cytology in the pleural effusion. Intrapleural instillation of adriamycin was followed by partial resolution, and administration of FEMP achieved complete disappearance of both pleural metastasis and pleural effusion.     

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.     

重组人血管内皮抑制素胸膜腔内注射治疗癌性胸水的临床观察

目的：探讨胸膜腔内注入重组人血管内皮抑制素（恩度）治疗癌性胸水的临床疗效。方法：对２００７年９月～２００８年９月在我科住院确诊的５例癌性胸水患者予胸膜腔内注入恩度治疗,于注药前及注药后第１天、注药后１月观察记录患者症状、毒副反应并判断疗效。结果：５例癌性胸水患者均为女性,肺癌３例,乳腺癌２例,年龄４０～７３岁,４例有效,１例未评价,均无毒副反应发生。结论：胸膜腔内局部注入恩度治疗癌性胸水有一定疗效且毒副反应少,对于无法化疗或化疗无效的癌性胸水患者是一种较好的治疗选择。     

Intraperitoneal and intrapleural gemcitabine in patients with advanced pancreatic cancer

We performed intraperitoneal and intrapleural dosing gemcitabine (GEM) to eight patients with advanced pancreatic cancer having peritoneal or pleural carcinomatosis and evaluated its actions and safety. GEM (500 mg/m2) was infused into the abdominal cavity or thoracic cavity after drainage of peritoneal or pleural effusion. We checked the change of serum GEM concentration and the side effects after the GEM administration. Then, we repeated the GEM administration observing their systematic symptoms and evaluated the alteration of peritoneal or pleural effusion and cytology. Plasma concentration of GEM by infusing into the abdominal cavity or thoracic cavity was lower than by intravenous injection. In three of the five cases of peritoneal carcinomatosis, intraperitoneal administration revealed a decrease of peritoneal effusion. In two of the three cases of pleural carcinomatosis, intrapleural administration revealed a decrease of pleural effusion. Four cases had leukocytopenia of grade 1/2, three cases had thrombocytopenia, and two cases had alopecia as side effects, although all of them were minor side effects. Intraperitoneal and intrapleural dosing GEM had minor side effects and could improve QOL for the patients with advanced pancreatic cancer associated with peritoneal or pleural carcinomatosis.     

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.     

射频热疗联合胸腔灌注药物治疗乳腺癌致恶性胸腔积液的临床观察

目的： 观察射频热疗联合胸腔灌注华蟾素、顺铂对乳腺癌所致恶性胸腔积液患者的临床疗效和不良反应。方法：62例确诊为乳腺癌伴恶性胸腔积液患者随机分为两组,热疗组32例患者采用射频热疗联合华蟾素与顺铂胸腔灌注治疗,对照组30例患者仅采取华蟾素与顺铂胸腔灌注治疗,治疗进行一月后对两组患者进行近期疗效率及Kamofsky（KPS）评分对比研究。结果：热疗组近期疗效总有效率为87.5％,优于对照组的66.7％;热疗组KPS提高率(93.8%)明显高于对照组(70.0%),差异均具有统计学意义(P<0.05)。两组不良反应发生率差异无统计学意义。结论：射频热疗联合胸腔灌注顺铂和华蟾素明显提高了乳腺癌致恶性胸腔积液的治疗效果,患者的生存质量得到明显改善,是一种具有临床应用价值的治疗方法。     

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。     

Modified intrapleural cisplatin treatment for lung cancer with positive pleural lavage cytology or malignant effusion

OBJECTIVES: We evaluate the efficacy and safety of the modified intrapleural cisplatin treatment for lung cancer patients with positive pleural lavage cytology or malignant effusion. METHODS: The treatment was performed for seven patients with malignant effusion and 18 patents with positive pleural lavage cytology. After pulmonary resection, the pleural cavity was filled with cisplatin with a normal saline solution for 30 min. Complications and survival of the patients were evaluated. RESULTS: The chest tube duration were significantly prolonged in the treatment (CDDP) group (5.7 +/- 3.6 vs. 2.8 +/- 2.6 days). We had one operative death that developed a bronchial fistula; however, the other complications were not severe. The mortality rate was 4% and the morbidity rate was 60%. We experienced two carcinomatous pleuritis in the CDDP group. The median survival time of the CDDP group was 47.0 +/- 11.1 months and the 3- and 5-year survival rate was 52.6% and 11.3%, respectively. CONCLUSIONS: We were able to perform this treatment for these advanced lung cancer patients, which had the preventive effect of carcinomatous pleuritis. This therapy shows the possibility of a treatment that might lead to an improvement in the prognosis of these patients, without causing severe complications.     

A case of scirrhous carcinoma of the stomach with malignant pleural and peritoneal carcinomatosis responding to the local administration of docetaxel (TXT)

We report the case of a 34-year-old woman who underwent total gastrectomy for scirrhous carcinoma in the stomach (T4, N0, H0, CY1, P1, Stage IV). Despite adjuvant chemotherapy with TS-1 and/or CDDP, ascites caused by peritoneal carcinomatosis increased four months after gastrectomy. Therefore, intraperitoneal administration of docetaxel (TXT) at a dosage of 45 mg/m2 was applied. This therapy successfully maintained her good quality of life by inhibiting the increase of ascites without any severe adverse side effects for more than six months. When the left effusion from pleural carcinomatosis appeared nine months after the surgery, the intrathoracic administration of TXT succeeded in inhibiting the increase of pleural effusion over five months or more. In this case, intraperitoneal and intrapleural administrations of TXT were effective and temporarily improved the patient's quality of life without any side effects. We thought that the local administration of TXT was a useful treatment without severe toxicities for malignant pleural effusion and ascites in scirrhous carcinoma of the stomach.     

Response and pharmacokinetics of cisplatin instilled into the pleural cavity

The response and pharmacokinetics of cisplatin instilled into the pleural cavity were studied in 11 patients with malignant pleural effusion; 10 patients had primary lung cancer and one had breast cancer. All of them were adenocarcinoma histologically. In five of the 11 patients effusion disappeared and its cytology became negative for malignancy after four weeks. In the other six patients effusion was reduced and its cytology became negative for malignancy after four weeks. Toxicity was almost similar to that in systemic administration of cisplatin but a few patients had chest pain and fever possibly due to local irritation. The pharmacokinetics showed that a high concentration of cisplatin (free-form, 48.9 micrograms/ml) was maintained over a long period (free from (t 1/2) beta = 33.6 hours) in the pleural cavity. This was regarded as the reason for the high response to this therapy. The intrapleural instillation of cisplatin into the pleural cavity therefore seems to be an effective modality for malignant pleural effusion.     

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.     

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.     

康莱特腔内注射治疗恶性胸腔积液的临床观察

目的:探讨康莱特(KLT)腔内注射对恶性胸腔积液治疗的价值.方法: 观察27例恶性胸腔积液患者腔内注射KLT后的疗效、不良反应及外周血免疫指标变化.结果: KLT腔内注射的有效率77.7%,不良反应为发热和胸痛,分别占11.1%与 3.7%.59.2%患者KPS评分增高.中位缓解4.6个月,中位生存期7个月.结论: KLT腔内注射对恶性胸腔积液有效,不良反应少,适用于老年体弱经、全身情况较差的恶性胸腔积液患者胸腔内局部治疗.     

康莱特腔内注射治疗恶性胸腔积液的临床观察

目的：探讨康莱特（KLT）腔内注射对恶性胸腔积液治疗的价值。方法：观察27例恶性胸腔积液患者腔内注射KLT后的疗效、不良反应及外周血免疫指标变化。结果：KLT腔内注射的有效率77．7％,不良反应为发热和胸痛,分别占11．1％与3．7％。59．2％患者KPS评分增高。中位缓解4．6个月,中位生存期7个月。结论：KLT腔内注射对恶性胸腔积液有效,不良反应少,适用于老年体弱经、全身情况较差的恶性胸腔积液患者胸腔内局部治疗。     

胸腔热灌注化疗治疗肺癌胸腔积液的临床观察

目的 观察胸腔热灌注化疗对比胸腔置管化疗治疗肺癌所致恶性胸腔积液的临床疗效及不良反应.方法 纳入103例肺癌胸腔积液患者,胸腔热灌注化疗组65例,胸腔置管化疗组38例.观察胸腔积液控制率、胸腔积液进展时间、胸腔积液中血管内皮生长因子(VEGF)浓度与疗效的关系以及不良反应发生情况.结果 热灌注化疗组和置管化疗组的胸腔积液控制率分别为81.5％和52.6％,差异有统计学意义(x2=9.834,P=0.002).两组患者的中位胸腔积液进展时间分别为3.10个月和2.15个月,差异有统计学意义(x2=10.512,P=0.001).胸腔积液中VEGF低浓度患者接受胸腔热灌注化疗和腔内置管化疗后的中位胸腔积液进展时间分别为3.34个月和2.20个月,差异有统计学意义(x2=9.409,P=0.002),但VEGF高浓度亚组,两种治疗方法的中位胸腔积液进展时间分别为2.85个月和2.10个月,差异无统计学意义(x2=2.429,P=0.119).两组患者的不良反应主要为消化道不良反应、乏力及血液毒性,热灌注化疗组患者乏力较置管化疗组常见(67.7％∶13.2％;x2 =28.595,P＜0.001).结论 胸腔热灌注化疗治疗肺癌所致恶性胸腔积液较常规腔内置管化疗提高了胸腔积液控制率,且可延长胸腔积液进展时间,不良反应易于耐受,胸腔积液进展时间延长在胸腔积液VEGF低浓度亚组中尤为明显,VEGF可作为胸腔热灌注化疗的疗效预测因素.     

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.     

榄香烯乳及顺铂治疗肺癌所致双胸腔积液的临床对比观察

为对比顺铂（ＤＤＰ）与榄香烯乳（Ｌｘ）在治疗肺癌所致恶性胸腔积液的效果。１９９５年１２月至１９９７年１２月收治肺癌所致恶性双侧胸腔积液１７例，左侧注入ＤＤＰ，右侧注入Ｌｘ。结果表明：有效率左侧胸腔５８％，右侧９４％（Ｐ＜０．０５）。右侧胸膜增厚明显高于左侧（Ｐ＜０．０５）。结论是Ｌｘ治疗肺癌所致恶性胸腔积液效果好于ＤＤＰ，胸膜增厚与疗效有关。     

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.