培美曲塞联合顺铂治疗恶性间皮瘤的疗效分析

 【摘要】　目的　回顾分析培美曲塞（PEM）联合顺铂（DDP）治疗恶性胸膜间皮瘤（MPM）的疗效。方法　将64例MPM患者分为2组,PEM组（32例）予PEM联合DDP,DDP组予以单纯DDP。分析两组有效率、无进展生存期（DFS）及总生存期（OS）。结果　两组患者化疗期间均未见明显不良反应,治疗后PEM组及DDP组有效率分别为56.25 %（18／32）、21.88 %（7／32）,差异有统计学意义（χ2＝7.943,P＜0.05）。PEM组较DDP组DFS延长（P＝0.033）。治疗后PEM组OS较DDP组高（P＝0.041）。结论　PEM联合DDP在延长MPM患者DFS及提高生存率方面有一定作用。     

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience

Background

The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients.

Methods

Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS = 0-2, adequate organ function, measurable disease.Chemotherapy was gemcitabine 1000 mg/m² days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m² or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan.

Results

Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2).The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75).Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%).

Conclusion

Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.     

Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma

Background: Prognosis for patients with malignant pleural mesothelioma (MPM) remains poor and such patients require intensive treatment. Few studies have examined hyperthermia for MPM. The present study investigated the feasibility of hyperthermia combined with weekly chemo-radiotherapy for patients with MPM and estimated the efficacy of this regimen.

Methods: A total of 11 patients (median patient age was 67 and all had pleural effusion) with MPM were enrolled in this study. The treatment regimen comprised of weekly thermo-radiotherapy with intra-thoracic chemotherapy 2–5 times at initiation of treatment. Hyperthermia was performed once per week for ～60?min. Hemithorax external radiotherapy was administered once weekly on the same day as hyperthermia and just before thermochemotherapy. Median total radiation dose was 6?Gy (range, 2–10?Gy). Chemotherapy was administered into the thoracic cavity through a tube. Chemotherapeutic agents administered were CDDP for seven patients, carboplatinum (CBDCA) for three patients and both CDDP and CBDCA for one patient. Dose of CDDP was 50?mg/body and dose of CBDCA was 200–300?mg?m^?2. Response rate and median survival time (MST) and palliative effect were investigated.

Results: Complete response was not achieved in any of the 11 patients. Partial response was achieved in three of 11 patients (27.3%), SD in six patients (54.5%) and PD in two patients (18.2%). There was no correlational relationship between thermal parameters and response. MST was 27.1 months. Pleural fluid decreased in all patients after therapy, while all patients displayed improved performance status and could be discharged from hospital. Patients with partial response had a relatively longer survival time than SD or PD. All patients underwent the complete course of treatment and only one of 11 patients developed grade 4 thrombocytopenia.

Conclusion: It was therefore concluded that hyperthermia combined with intra-thoracic chemotherapy using cisplatinum or carboplatinum may be tolerable. This approach appears effective and more acceptable for patients with MPM with pleural effusion than other multi-modality therapy.     

Retreatment with pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM): a second line treatment option

The role of second line treatment in malignant pleural mesothelioma (MPM) is currently undefined. We present four cases of patients who had durable responses from pemetrexed-based chemotherapy who were retreated with a similar regimen upon progression of their mesothelioma. This case series explores the possible role of retreatment with pemetrexed-based chemotherapy as a second line therapeutic option in MPM.     

恶性胸膜间皮瘤靶向治疗进展

恶性胸膜间皮瘤（MPM）是胸膜罕见的恶性肿瘤,由于其潜伏期约为20年,目前正是该疾病的高发阶段.由于该疾病发现时大部分已处于晚期,除了经典的培美曲塞联合顺铂一线化疗方案疗效确定之外,手术、放疗及二三线化疗疗效仍未知.近年来发展迅猛的分子靶向治疗又为MPM的个体化治疗提供了新的方向.     

恶性胸膜间皮瘤远期疗效的影响因素分析

背景与目的:恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)是一种少见的恶性肿瘤,但预后差。本文分析MPM的治疗效果,探讨影响其预后的因素。方法:1988年1月～2001年12月中山大学肿瘤医院收治的经病理组织学或细胞学确诊的MPM24例,其中12例单纯接受以DDP为基础的方案化疗1～6个疗程,7例接受手术治疗和以DDP为基础的术后化疗1～6个疗程,5例接受手术治疗和术后放射治疗。用Kaplan-Meier法计算生存率,用log-rank法比较各组的生存率,应用Cox模型进行多因素分析。结果:24例患者1、3、5年生存率分别为37.5%、20.8%和4.2%,中位生存期9.0个月。单纯化疗组12例患者的1、3、5年生存率分别为16.7%、0和0,中位生存期为5.0个月;手术加化疗组7例患者的1、3、5年生存率分别为28.6%、14.3%和0,中位生存期为10.0个月;手术加放疗组5例患者的1、3、5年生存率分别为100.0%、80.0%和20.0%,中位生存期为42.0个月。3组生存率比较有显著性差异(χ2=11.93,P=0.00)。影响MPM预后的因素有临床分型(P=0.04)和治疗方法(P=0.00)。结论:临床分型和治疗方法是影响MPM预后的独立因素。     

An overview of neoadjuvant chemotherapy in the multimodality treatment of malignant pleural mesothelioma

Malignant Pleural Mesothelioma (MPM) is an aggressive tumour with poor prognosis and increasing incidence in industrialized countries because of the previous widespread exposure to asbestos fibres and to the long lag period from time of exposure and the diagnosis of the disease.     

恶性胸膜间皮瘤的外科治疗

目的　恶性胸膜间皮瘤的治疗尚无统一方案 ,手术切除仍是主要的治疗手段。本文探讨了恶性胸膜间皮瘤的手术方式、手术指征 ,以及影响术后生存的因素。方法　收集本院自 1985年以来手术治疗的恶性胸膜间皮瘤患者的资料 ,对临床表现、TNM分期、细胞类型、手术方式、生存期等分析 ,研究胸膜外全肺切除和胸膜切除两种不同手术方式以及不同分期、不同细胞类型对预后的影响。结果　 33例手术治疗者中胸膜外全肺切除术 16例 ,胸膜切除术 17例 ,总中位生存期为 2 1个月 ,2年生存率和 5年生存率分别为 36 .6 %和 13.3% ,不同手术方式之间术后生存期差异无显著性 ;不同TNM分期之间生存期差异有显著性 (P =0 .0 4 2 8)。结论　无论胸膜外全肺切除还是胸膜切除 ,都只能达到肉眼下的完全切除 ,可缓解症状 ,并为综合治疗创造条件。两种手术方式对预后的影响差异无显著性。早期诊断和尽早手术治疗是取得良好效果的关键。     

Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma

Background

Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients.

Methods

Vinorelbine 25 mg/m² was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity.

Results

Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as >2L treatment. The median age was 69 years (range 45–80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR_{0 vs. 1–2} 0.50; 95%CI: 0.3–0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR_{FL-PFS>6ms vs. <6ms} 0.50; 95%CI: 0.3–0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients.

Conclusions

Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥6 months.     

培美曲塞与卡铂静脉化疗联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤的临床观察

目的　评价培美曲塞与卡铂化疗同时联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤（ＭＰＭ）合并胸腔积液的疗效与安全性。方法　回顾性分析１５例ＭＰＭ合并胸腔积液患者的临床资料,具体用药：培美曲塞５００ｍｇ／ｍ２,ｄ１;卡铂（ＡＵＣ＝５）ｄ２,每２１天重复;同时引流尽胸腔积液,榄香烯乳２００ｍｇ／ｍ２胸腔注入,ｄ１或ｄ８。结果　１５例患者中,１３例（８６.７％）胸腔积液得到控制,１０例（６６.７％）胸腔积液癌细胞检查由阳性转为阴性;获ＣＲ４例,ＰＲ６例,ＳＤ３例,ＰＤ２例;总有效率为６６.７％,疾病控制率为８６.７％,中位无进展时间为５.０个月,中位总生存时间为１１.１个月,１年生存率为３６.０％。主要毒副反应为骨髓抑制、发热、胸痛、皮疹,多为１～２级,支持对症处理后均可恢复。结论　培美曲塞联合卡铂化疗同时榄香烯乳胸腔灌注治疗ＭＰＭ合并胸腔积液有较好的疗效,毒副反应轻,值得临床推广应用。     

胸膜恶性间皮瘤临床病理分析

 目的 对胸膜恶性间皮瘤进行临床病理分析，提高诊断及治疗水平，减少误诊率。方法 收集１９７５～１９９９年诊治病例，复习Ｘ光、Ｂ超及细胞病理资料。结果 ８０％病人临床上有胸痛且进行性加重，并有胸腔积液。Ｘ光有局限性胸膜增厚，胸水显示出现恶性瘤细胞，病理切片有双向分化特点。结论 对中年人胸部剧烈疼痛伴有胸腔积液时，应首先考虑本瘤，该瘤的确诊应依赖临床、影像学及细胞病理学。     

Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma

The aim was to evaluate the activity of cisplatin and vinorelbine in previously untreated, inoperable patients having histologically verified malignant pleural mesothelioma (MPM), normal organ function, and performance status 0-2. Treatment was vinorelbine 25 mg m(-2) i.v. weekly and cisplatin 100 mg m(-2) i.v. every 4 weeks with hydration and standard prophylactic antiemetic treatment. Patients gave written informed consent. Characteristics of 54 consecutive patients were: males 85%, epithelial subtype 74%, IMIG stages III and IV 35 and 46%, performance status 0, 1, and 2, 26, 69, and 6%, and median age 63 years (31-78 years). CTC grade 3 or 4 toxicity occurred with respect to leukocytopenia (48% of patients, grade 4 in 13%), nausea (13%), neurotoxicity (11%), nephrotoxicity (4%), and other toxicities (9%). There were no toxic deaths. The median number of cycles was four. The fraction of patients alive at 1-, 2-, and 3-years were 61, 31, and 4%, respectively, and median survival and median time to progression were 16.8 months (0.5 to 46.4 +months) and 7.2 months (1.6 to 40.6 + months). There were two CRs and 14 PRs (response rate 29.6%). Cisplatin and intravenous vinorelbine is a highly active regimen in MPM with a response rate and survival comparable to the most active regimens so far reported.     

Feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma from a viewpoint of dose distribution analysis

PURPOSE: To investigate the feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma (MPM) from a viewpoint of dose distribution analysis using Simulation Environment for Radiotherapy Applications (SERA), a currently available BNCT treatment planning system. METHODS AND MATERIALS: The BNCT treatment plans were constructed for 3 patients with MPM using the SERA system, with 2 opposed anterior-posterior beams. The (10)B concentrations in the tumor and normal lung in this study were assumed to be 84 and 24 ppm, respectively, and were derived from data observed in clinical trials. The maximum, mean, and minimum doses to the tumors and the normal lung were assessed for each plan. The doses delivered to 5% and 95% of the tumor volume, D(05) and D(95), were adopted as the representative dose for the maximum and minimum dose, respectively. RESULTS: When the D(05) to the normal ipsilateral lung was 5 Gy-Eq, the D(95) and mean doses delivered to the normal lung were 2.2-3.6 and 3.5-4.2 Gy-Eq, respectively. The mean doses delivered to the tumors were 22.4-27.2 Gy-Eq. The D(05) and D(95) doses to the tumors were 9.6-15.0 and 31.5-39.5 Gy-Eq, respectively. CONCLUSIONS: From a viewpoint of the dose-distribution analysis, BNCT has the possibility to be a promising treatment for MPM patients who are inoperable because of age and other medical illnesses.     

Advances in the biology of malignant pleural mesothelioma

Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.     

Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma

BACKGROUND: Promising results with trimodality therapy combining surgery, chemotherapy, and radiotherapy have been obtained in the management of patients with malignant pleural mesothelioma (MPM). However, the histologic subtype has to be taken into account because of its influence on prognosis. The aim of the current study was to analyze retrospectively the accuracy, sensitivity, and specificity of preoperative thoracoscopy for diagnosis of the histologic subtype of MPM. METHODS: The histologic reports from all consecutive patients undergoing 'intent-to-treat' surgery from 3 institutions as well as the initial pathologic diagnosis obtained using thoracoscopy were reviewed and compared after institutional review board approval. All cases of MPM were confirmed by a panel of pathologists. RESULTS: Ninety-five patients were included in the current study. Of these 95 patients, 75 underwent extrapleural pneumonectomy, 9 patients underwent pleurectomy/decortication, and 11 patients underwent pleurectomy. Of the 95 patients with a final diagnosis of MPM, 80 (84.2%) were classified as having epithelial and 15 (15.8%) as having biphasic subtype. Among the 87 patients classified as having MPM of epithelial subtype after the initial thoracoscopy, 75 cases (86.2%) were confirmed to be a true histologic diagnosis and 12 cases (13.8%) were found to be of biphasic subtype at final diagnosis. One patient with a biphasic subtype at initial thoracoscopy was found to have MPM of epithelial subtype after surgery. The sensitivity and specificity values of an epithelial subtype diagnosis after thoracoscopy were 94% and 20%, respectively, with a positive predictive value of 86% and a negative predictive value of 37%. Conversely, the sensitivity and specificity values of a biphasic subtype diagnosis after thoracoscopy were 20% and 98%, respectively, with a positive predictive value of 75% and a negative predictive value of 87%. CONCLUSIONS: Pleural biopsy performed using thoracoscopy is considered to be the cornerstone of the diagnosis and pleural staging of MPM. However, this procedure appears to be less efficient in diagnosing the histologic subtype as either epithelial or biphasic.     

恶性胸膜间皮瘤的治疗现状

恶性胸膜间皮瘤(MPM)是一种罕见的恶性肿瘤。外科手术是治疗的主要方式,术后辅助放疗能控制肿瘤的局部复发,并延长生存期。单纯放疗仅用于减症及预防有创性诊断后的局部种植。辅助化疗的作用不确切。化疗对晚期MPM有一定的作用,阿灵达与顺铂的联合应用将化疗的有效率从20%提高至40%以上,并能改善存活率、疾病进展时间和生活质量等,为该病的治疗带来了希望。应该继续开发新的靶向治疗药物,使MPM的治疗取得更多进展。     

Radiological manifestations of malignant pleural mesothelioma

Malignant pleural mesothelioma has had a rising incidence in Australia over the past 40 years. This pictorial essay gives a brief account of the condition, summarizes the various radiological manifestations and aims at increasing the awareness of a disease that is expected to reach its peak incidence in the early decades of the twenty‐first century.     

Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is expected to increase due to delayed control of occupational exposure to asbestos in Japan. We investigated the use of triplet combination chemotherapy with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR) for the treatment of Japanese patients with MPM. METHODS: From December 2000 to August 2003, 12 patients received the following regimen: CDDP 40 mg/m(2), GEM 800 mg/m(2) and VNR 20 mg/m(2) on days 1 and 8 every 4 weeks. Among the 12 patients, six selected patients underwent an extrapleural pneumonectomy (EP) after a median of three cycles of triplet chemotherapy. RESULTS: The overall response rate for all patients and the response rate for chemotherapy-naive cases were 58 and 67%, respectively. The median survival time and survival rate at 2 years for all patients were 11 months and 50%, respectively. The 2-year survival rates for the patients with and without EP were 83.3 and 16.7%, respectively. CONCLUSIONS: Triplet chemotherapy with CDDP, GEM and VNR was thus found to be highly effective for patients with MPM and its toxicity was manageable. A multi-institutional phase II trial is now being planned to establish the effectiveness of this new regimen in chemotherapy-naive patients with MPM.