Standard therapy for the treatment of malignant pleural mesothelioma

Almost all of the established cytotoxic agents have now been examined both as single-agents and in combination chemotherapy regimens as treatment approaches for malignant pleural mesothelioma (MPM). Until recently, only few agents have consistently produced objective response rates greater than 20%, and no agent has improved median survival beyond 10 months. The recent development of several new cytotoxic agents, such as the novel antimetabolite pemetrexed, has yielded encouraging results. In particular, pemetrexed produces response rates of up to 45%, and increases median survival to over 12 months when used in combination with cisplatin. This doublet-based chemotherapy regimen is now the standard therapy for the first-line treatment of MPM.     

Gene therapy for malignant pleural mesothelioma

Gene therapy for mesothelioma is currently in its adolescence. The expansion of knowledge regarding molecular aspects of mesothelioma carcinogenesis has facilitated the development of promising gene therapy modalities that target specific oncoproteins and mutant tumor suppressor genes. Although implementation of any of these gene therapy approaches as part of standard medical care for patients who have mesothelioma remains years in the future, the field is finally progressing toward more definitive phase II/III efficacy studies. Unfortunately, the marginal benefits garnered from standard anticancer treatments in mesothelioma argue strongly for continued participation in clinical studies of various experimental approaches, particularly gene therapy. These trials serve multiple purposes: to establish safety, determine proper dosing, evaluate for efficacy, and, in an iterative fashion, guide future avenues of laboratory investigation.     

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。     

Radiation therapy for malignant pleural mesothelioma

The treatment of malignant pleural mesothelioma with radiation has always been a technical challenge. For many years, conventional radiation therapy was delivered after extrapleural pneumonectomy with acceptable results. Novel radiation treatment techniques, such as intensity modulated radiation therapy (IMRT) were introduced, but the early experience with IMRT demonstrated troubling toxicity. Recent reports from institutions have demonstrated that with greater experience, IMRT, both in the setting of extrapleural pneumonectomy or pleurectomy, can be delivered safely. A recent study, SAKK 17/04, questions the role of using radiation after extrapleural pneumonectomy.     

Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule-1 (ICAM-1) expression tended to be more susceptible to CVA11-induced cytotoxicity, and a neutralizing antibody to ICAM-1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal-regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11-mediated cytotoxicity. Furthermore, CVA11 infection-triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin-1β and damage-associated molecular patterns such as calreticulin, high-mobility group box-1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM-1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM.     

Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells

Background:

A major problem with cisplatin treatment is the development of acquired-drug resistance of the tumour cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the membrane glycolipid globotriasosylceramide (Gb3), a molecule associated with drug resistance. Cisplatin- and VT-1-induced apoptosis involves mitogen-activated protein kinase (MAPK) activation, and deactivation of MAPKs is associated with cisplatin resistance. This study aimed to investigate whether a sub-toxic concentration of VT-1 could enhance cisplatin-induced apoptosis and overcome acquired-cisplatin resistance in cultured cancer cell lines.

Method:

P31 and H1299 cells with corresponding cisplatin-resistant sub-lines (P31res/H1299res) were incubated with VT-1 and/or cisplatin followed by determination of Gb3 expression, cell viability, apoptosis, and signalling pathways.

Results:

Cells from the resistant sub-lines had elevated Gb3 expression compared with the parental cell lines, and cisplatin further increased Gb3 expression, whereas VT-1 reduced the percentage of Gb3-expressing cells. Combination of cisplatin and sub-toxic concentrations of VT-1 led to a super-additive increase of cytotoxicity and TUNEL staining, especially in the cisplatin-resistant sub-lines. Blockade of Gb3 synthesis by a Gb3 synthesis inhibitor not only led to eradicated TUNEL staining of P31 cells, but also sensitised P31res cells to the induction of apoptosis by cisplatin alone. Cisplatin- and VT-1-induced apoptosis involved the MAPK pathways with increased C-Jun N-terminal kinase and MAPK kinase-3 and -6 phosphorylation.

Conclusions:

We show the presence of Gb3 in acquired-cisplatin resistance in P31res and H1299res cells. Cisplatin up-regulated Gb3 expression in all cells and thus sensitised the cells to VT-1-induced cytotoxicity. A strong super-additive effect of combined cisplatin and a sub-toxic concentration of VT-1 in cisplatin-resistant malignant pleural mesothelioma cells were observed, indicating a new potential clinical-treatment approach.     

Multidisciplinary treatment of malignant pleural mesothelioma

The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease.     

Advances in the systemic therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.     

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.     

Multimodality treatment of diffuse malignant pleural mesothelioma

Diffuse malignant pleural mesothelioma (DMPM) is a challenging disease in all of its aspects, from presentation and diagnosis to staging and treatment. Single-modality therapy was the initial approach to this disease. It generally has not been effective in changing the natural history of DMPM. As a result, multimodality regimens involving surgery with radiation, chemotherapy, or immunotherapy delivered regionally or systemically have been evaluated. Randomized controlled studies comparing various strategies are lacking and, thus, the debate continues regarding the effectiveness of different treatment approaches.     

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。     

恶性胸膜间皮瘤化疗进展

目的总结国内外对恶性间皮瘤(malignant pleural mesothelioma,MPM)内科治疗研究的现状。方法检索PubMed及CNKI期刊全文数据库检索系统,以"胸膜间皮瘤、内科治疗和化疗"等为关键词,检索2008-01-2013-10的相关文献,共检索到英文文献36条,中文文献22条。纳入标准:1)MPM的一线化疗;2)MPM的二线化疗;3)MPM的新辅助化疗;4)MPM的腔内化疗。根据纳入标准符合分析的文献37篇。结果培美曲塞+顺铂为标准一线化疗方案,以下药物也可用于MPM的一线化疗:1)培美曲塞+卡铂;2)吉西他滨+顺铂;可用于培美曲塞禁忌患者;3)单药一线化疗药物包括培美曲塞与长春瑞滨。当前尚没有确切MPM的标准二线化疗方案,对于曾通过接受一线含培美曲塞能延长无进展生存期的患者,再次接受含培美曲塞方案化疗或许不失为一种好的选择。术前新辅助化疗可提高术后局部控制率,降低复发及远处转移率。备选方案有吉西他滨联合铂类和铂类联合抗叶酸药物。术中腔内化疗(腔内热灌注顺铂等)已在临床中运用,可提高局部控制率。结论化疗是治疗MPM的主要手段,虽然恶性胸膜间皮瘤的诊断与治疗处于发展状态,但患者的预后仍较差。目前缺少Ⅱ、Ⅲ期的随机对照研究,需要前瞻性研究进一步评估不同化疗方案的毒副作用及对生存的影响。     

SEOM guidelines for the treatment of malignant pleural mesothelioma

Mesothelioma is a rare malignant tumour. Asbestos is the principal aetiological agent of malignant pleural mesothelioma (MPM) (∼80% of cases). The incidence of MPM is still increasing and will peak within the next 10 years. There are three main histological types of MPM: epithelial (∼60%), sarcomatous and mixed. There is no standard approach for patients with MPM. Surgery (radical extra-pleural pneumonectomy or pleurectomy/decortication) may be part of the initial treatment for carefully selected patients, generally combined with neoadjuvant or adjuvant chemotherapy and/or adjuvant radiotherapy, and should only be performed by experienced thoracic surgeons as part of a multidisciplinary team. Radiotherapy could be used as prophylaxis to reduce the incidence of recurrence at sites of diagnoses or therapeutic instrument insertion, in a multimodal treatment to improve locoregional control and to palliate symptoms. Based on the better compliance of neoadjuvant chemotherapy, lower rate of surgical morbidity and the possibility to select the optimal patients to be submitted to surgery, a neoadjuvant strategy is a better option than adjuvant chemotherapy, although there is no standard optimal sequence and types of treatment for multimodal therapy. In patients with no resectable disease, chemotherapy is the best option with platinum and pemetrexed or raltitrexed. At this time there is no widely approved salvage therapy.     

Staging and response to therapy of malignant pleural mesothelioma

Earlier staging systems tended to concentrate on advanced malignant pleural mesothelioma (MPM) and considerable variation arose among the different systems. This was addressed in 1997 when the International Mesothelioma Interest Group (IMIG) staging system was approved. This is not a perfect system as many of the distinctions it makes cannot be identified by current computed tomography (CT) and magnetic resonance imaging (MRI) scanning. However presurgical staging using CT and MRI can be useful in delineating the extent and volume of disease and in detecting unexpected advanced disease as well as alerting clinicians to the possibility of early stage malignant pleural mesothelioma. Patients response to therapy can be measured using the response evaluation criteria in solid tumors (RECIST) criteria involving multiple measurements of a single diameter of tumour thickness.     

Recent progress in treatment of malignant pleural mesothelioma]

Incidence of malignant pleural mesothelioma will rise until 2030-2040 because the elapsed time between exposure and diagnostic is up to several decades. Prognosis remains very poor with median survival less than one year and five-year survival not exceeding 5%. As compared to 1999, standart treatment adds chemotherapy with cisplatin and pemetrexed to local radiotherapy for prevention of local seeding after invasive diagnostic procedures. Despite various growth factors and their receptors are involved in malignant mesothelioma, first clinical trials of targeted therapies reported poor results. Multimodality therapy with extrapleural pneumonectomy and radiation therapy (+/-chemotherapy) can be of benefit in subgroups of patients but it cannot be recommended in a routine approach. As compared to bronchial carcinoma, inclusion of patients in clinical trials (using intensity-modulated radiation therapy) is the only way to somewhat improve results.     

Advances in diagnosis and treatment of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive but relatively rare malignancy with median survival ranging from 8 to 14 months depending on stage and presentation of disease. New diagnostic procedures are urgently needed, selecting patients in earlier stages to evaluate therapeutic approaches which combine chemotherapy, surgery and radiotherapy. Combination chemotherapy represents the only resource available for advanced disease. The combination of cisplatin and pemetrexed is the treatment of choice. This review summarizes the latest developments in diagnostic techniques and the available therapeutic options for the management of MPM. Particular attention is given to the molecular basis of biologically targeted therapies to be used in the future.     

Thrombocytosis in malignant pleural mesothelioma

The prevalence of thrombocytosis (defined as a platelet count above 400,000/mm3 in at least two examinations) and the prevalence of thromboembolism were retrospectively investigated in a series of 41 patients with malignant pleural mesothelioma and in 40 subjects with non small cell lung carcinoma. All the patients were examined at necropsy. The mesothelioma patients showed a higher prevalence of thrombocytosis (56.8% vs 24.2%; p less than 0.01). However, the prevalences of thromboembolism were similar in the two groups of patients (36.6% and 32.5% respectively). Among those with mesothelioma the prevalence of thrombocytosis varied widely from one histological type to another (76.9% in mixed type, 57.1% in the epithelial, and 30% in the sarcomatous type), the difference between mixed and sarcomatous being statistically significant (p less than 0.01). Moreover, the mesothelioma patients of under 70 years had thrombocytosis more often than those over 70 (80% vs 29.4%; p less than 0.01).     

Glycosaminoglycan in malignant pleural mesothelioma

The quantitative analysis on glycosaminoglycan (GAG) in the tumor tissues of five patients with malignant pleural mesothelioma and in the pleural fluid of two patients was performed with the use of biochemical methods. In the tumor tissues, it was found that the average of the total amount of GAG was more than 7.9 times as high as that in adenocarcinoma of the lung, and that hyaluronic acid and chondroitin sulfate were main constituents of mesothelioma GAG. However, there was no significant difference in the content of dermatan sulfate and heparan sulfate between this neoplasm and adenocarcinoma. In the pleural fluid, the amount of hyaluronic acid was about 40 to 230 times higher than that in adenocarcinoma of the lung with the increment of chondroitin sulfate (11-87 times). These findings suggest that a marked increase in the total amount of GAG and the elevation of either the hyaluronic acid or the chondroitin sulfate level, or both, are characteristic abnormalities in malignant pleural mesothelioma.