Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: a multi-institutional phase II trial

To assess the effect and toxicity of hypotonic cisplatin treatment (HPT) consisting of the intrapleural administration of cisplatin in distilled water for malignant pleural effusion in patients with non-small-cell lung cancer (NSCLC). Non-small-cell lung cancer patients with cytologically proven and previously untreated malignant pleural effusion were enrolled into this study. Firstly, the lung was fully re-expanded by a tube thoracostomy, and then 25 mg cisplatin in 500 ml of distilled water was instilled through a chest tube and then the tube was clamped. After 1 h, the tube was declamped and allowed to drain. The chest tube was removed when the pleural effusion volume decreased to 200 ml or less per day. A complete response (CR) was considered to occur when the pleural effusion disappeared. A partial response (PR) was determined to occur when the volume of pleural effusion remained under (1/4) of hemithorax. The response at 4 weeks was evaluated by an extramural review. Out of 84 patients enrolled from February 1998 to August 2002, 80 patients were eligible and analysed in the present study. The toxicity of HPT was acceptable. Neither a haematological toxicity of any grade nor grade 4 nonhaematological toxicity was observed. Grade 3 nonhaematological toxicities were observed, including nausea (4%), vomiting (3%), pyothorax (1%) and dyspnoea (1%). The median time of drainage from HTP was 4 days. Twenty-seven (34%) and 39 (49%) patients achieved CR and PR, respectively, for an overall response rate of 83% (95% confidence interval, 74-91%). The median duration of the response was 206 days. The median survival time of all patients was 239 days. Hypotonic cisplatin treatment for malignant pleural effusion of NSCLC is therefore considered to be feasible and effective. A phase III study of HPT is thus warranted.     

Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies.

PURPOSE: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma. PATIENTS AND METHODS: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05. RESULTS: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid. CONCLUSIONS: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.     

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.     

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.     

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。     

A case of remission in diffuse pleural mesothelioma induced by anticancer chemotherapy with cisplatin and adriamycin

A 56-year-old man was admitted to our hospital with complaints of dyspnea and right pleural effusion. Malignant pleural mesothelioma was diagnosed, based on the high level of hyaluronic acid in the pleural fluid and manifestation of malignant cells by pleural needle biopsy. Anticancer chemotherapy with cisplatin and intrapleural injections of adriamycin against this mesothelioma was carried out because of the presence of stage III by Butchart's classification. Regression of the tumor, decrease of pleural fluid and decrease of LDH level in effusions were observed after this chemotherapy. Cisplatin was easily transported into the pleural fluid, and its concentration was maintained for a satisfactorily long period.     

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.      

Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.     

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。     

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。     

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。     

黏质沙雷氏菌苗治疗恶性胸腔积液的临床研究

目的 评价黏质沙雷氏菌苗（S311）治疗恶性胸腔积液的疗效及毒副反应。方法 取S311 10^9U(0.32mg)于第1,8,15天注入胸腔。观察4周,评价疗效和毒副反应。结果 34例患者中,完全缓解（CR）12例,部分缓解（PR）21例,总有效率97.1%(33/34)。毒副反应较轻,有发热（82．4％）、胸痛（52．9％）、恶心（26．5％）、呼吸困难（17．5％）、寒战（5．9％）及呕吐（2．9％）。结论 S311治疗恶性胸腔积液疗效较好,毒副反应可以耐受,可以安全用于临床。     

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.     

顺铂联合足叶乙甙治疗恶性胸腔积液60例

［目的］观察顺铂联合足叶乙甙联合治疗恶性胸腔积液的治疗效果。［方法］先将胸水尽量抽尽,将顺铂５０ｍｇ,足叶乙甙１００ｍｇ溶于生理盐水５０ｍｌ,胸腔内缓慢注射。［结果］６０例病人中,ＣＲ４４例,ＰＲ９例,总有效率８８．３％。［结论］顺铂联合足叶已甙胸腔化疗治疗恶性胸腔积液有效率高,毒副反应轻,是值得推广的疗法。     

转移性恶性胸腹腔积液患者肿瘤细胞中乳腺癌易感基因1mRNA的表达与铂类敏感性的关系

目的 研究乳腺癌易感基因1(BRCA1)在转移性恶性胸腹腔积液肿瘤细胞中的表达,并探讨BRCA1基因表达在铂类化疗疗效中的预测作用.方法 收集31例经病理确诊的恶性胸腹腔积液标本,分离原代肿瘤细胞.采用细胞计数试剂盒(CCK8)体外药物敏感性试验,检测顺铂(DDP)对原代肿瘤细胞的抗肿瘤作用,采用实时荧光定量PCR法检测肿瘤细胞中BRCA1 mRNA的相对表达水平.结果 BRCA1 mRNA在原代肿瘤细胞中的表达水平为0.618(0.014～18.063),DDP对原代肿瘤细胞的半数抑制浓度(IC50)为2.809 μg/ml (0.118～19.439 μg/ml).BRCA1 mRNA的表达及DDP对原代肿瘤细胞的IC50值与患者的年龄、性别、原发肿瘤类型、是否接受化疗以及积液类型均无关(均P＞0.05).BRCA1 mRNA的表达水平与DDP抵抗正相关,BRCA1 mRNA低表达者对DDP的敏感性高(r=0.786,P＜0.001).结论 检测BRCA1 mRNA的表达水平可以为转移性胸腹腔积液患者应用铂类药物化疗提供理论依据.

Abstract：

Objective To explore the mRNA expression of breast cancer susceptibility gene 1 (BRCA1) in tumor cells isolated from malignant pleural and peritoneal effusions, and the predictive role of BRCA1 related to the efficacy of cisplatin-based chemotherapy. Methods Tumor cells were isolated from malignant pleural and peritoneal effusions of 31 cancer patients. The response of these tumor cells to cisplatin was determined by CCK8 assay. Real time quantitative RT-PCR was used to examine the BRCA1 mRNA level in the primary culture cancer cells. Results The expression level of BRCA1 mRNA was 0.618(0.014-18.063)in primary culture tumor cells. The IC50 of DDP was 2.809 μg/ml in the primary culture tumor cells (0.118-19.439 μg/ml). Both BRCA1 mRNA expression and the tumor cells IC50 of DDP were not significantly related with patient age, gender, the type of primary tumor, whether to accept the chemotherapy and effusion type (P>0.05). The level of BRCA1 mRNA was negatively correlated with the chemosensitivity in terms of IC50 of cisplatin (P<0.001). Conclusion Assessment of expression level of BRCA1 mRNA may be useful in predicting the efficacy of cisplatin-based chemotherapy in patients with metastatic malignant effusions.     

RmhTNF联合顺铂与单用顺铂胸腔注射治疗恶性胸腔积液的比较

目的研究重组改构肿瘤坏死因子(rmhTNF) 顺铂及单用顺铂治疗恶性胸腔积液的疗效及毒性反应。方法两组所有病例均先采用中心静脉管胸腔置管术,胸水引流干净后,胸腔内分别注入rmhTNF 顺铂或单用顺铂,观察两组疗效及毒性反应。结果rmhTNF 顺铂组治疗恶性胸腔积液的有效率为92.5%,单用顺铂组为80.6%;两组毒副反应发生率分别为39.6%和41.9%。结论rmhTNF 顺铂组治疗恶性胸腔积液的疗效优于单用顺铂组,而毒副反应无差别。     

香菇多糖腹腔内注射联合体外高频热疗治疗恶性腹腔积液

目的观察生物反应调节剂香菇多糖联合体外高频热疗治疗恶性腹腔积液的临床疗效。方法A组：应用香菇多糖6—8mg／次,腹腔内注射,每周1次,体外高频热疗,每周2次,连续4周;B组：应用顺铂30—40mg／次,腹腔内注射,每周1次,体外高频热疗,每周2次,连续4周。结果A组14例中完全缓解4例（28．6％）,部分缓解6例（42．8％）,无效4例（28．6％）,总缓解率为71．4％;B组14例中完全缓解4例（28．6％）,部分缓解5例（35．7％）,无效5例（35．7％）,总缓解率为64．3％。两组均未见明显不良反应。结论生物反应调节剂香菇多糖治疗恶性腹腔积液疗效可靠。     

γ干扰素治疗恶性胸腹腔积液的临床观察

目的 观察γ干扰素治疗恶性胸腹腔积液的疗效。方法 经病理或细胞学证实的恶性胸腹水患者56例,尽量抽（放）净患者胸腹水后,胸膜腔内注入γ干扰素200－300万U＋0．9％盐水20ml,视胸腹水多少,5－10天后再重复治疗。结果 恶性胸水患者46例,CR：17（37．0％）,PR：17（37．0％）,NC：12（26．0％）,总有效率：CR＋PR：34（74．0％）。恶性腹水患者10例,CR：2例,PR：例,NC：4例。结论 γ干扰素治疗恶性胸腹腔积液发挥了生物反应调节剂局部治疗的优势,是治疗恶性胸腹水的又一有效药物。     

Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma and to characterize the pharmacokinetic profiles of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). METHODS: Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest period. The course of treatment was repeated every 28 days. After intravenous administration, the levels of CPT-11 and SN-38 in the plasma and pleural fluid were determined for each histologic subtype of mesothelioma. RESULTS: All patients were evaluable for response and toxicity. Four partial responses (response rate of 26.7%) with a median response duration of 25.9 weeks and 2 regressions of evaluable disease (overall response rate of 40%) were observed. The median survival time after chemotherapy was 28.3 weeks, and the median time to treatment failure was 22.1 weeks. The 1-year survival rate for all patients was 38.5%. Toxicity was well tolerated, and there were no treatment-related deaths. World Health Organization Grade 3 leukopenia occurred in 3 patients (20%), and Grade 1 or 2 diarrhea occurred in 3 patients (20%). There was no excess toxicity in patients with large pleural effusions compared with those with no pleural effusions. CPT-11 and SN-38 were detected in the pleural fluid 1 hour after intravenous administration. The maximum concentrations of CPT-11 and SN-38 in the pleural fluid were 36.5% and 75.8%, respectively, of the corresponding plasma values. CONCLUSIONS: The combination of cisplatin and CPT-11 had definite activity against malignant pleural mesothelioma and was well tolerated. The intravenous administration of CPT-11 produced adequate distribution of CPT-11 and its active metabolite SN-38 into the pleural fluid and allowed a higher concentration of the more active SN-38 to make contact with mesothelioma cells in the thoracic cavity. These results warrant further clinical evaluation of this combination chemotherapy for the treatment of malignant pleural mesothelioma in a confirmatory Phase II trial.     

化疗联合深部热疗治疗胸腔恶性积液的临床观察

目的：恶性胸腔积液是晚期肺癌的常见并发症，全身化疗联合胸腔内药物注射是治疗恶性胸腔积液最常用的方法之一，但存在疗效不稳定、药物毒副反应大等问题。本研究的目的是观察热疗联合化疗治疗恶性胸腔积液的疗效、毒副反应和患者的生活质量。方法：确诊为晚期肺癌所致恶性胸腔积液的初治患者60例，分为热化疗和单纯化疗两组。热化疗组：采用胸腔穿刺置入中心静脉导管术尽可能排尽胸水后，给予吉西他滨1000mg／m^2，d1、d8，胸腔注射顺铂40mg／次，隔日1次，共3次。胸腔局部化疗24h后采用TYHP700-Ⅰ体外高频热疗机进行患侧胸腔的深部热疗，根据患者实际耐受情况设定治疗功率300～1000W，治疗时间40～60min，每21天为1周期，共治疗4个周期。单纯化疗组：给予吉西他滨1000mg／m^2，d1、d8，胸腔注射顺铂40mg／次，隔日1次，共3次，每21天为1周期，共治疗4个周期。结果：热化疗组控制胸水的总有效率为90．0％，单纯化疗组为66．7％（P=0．024）。两组毒副反应仅见一过性发热、轻度气胸和胸膜反应等。两组生活质量好转率分别为72．0％和40．0％（P=0．013）。结论：采用热疗联合化疗治疗恶性胸腔积液疗效确切，毒副反应小，安全性高。