Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.     

培美曲塞与顺铂化疗联合苦参治疗胸膜间皮瘤18例报道

目的:评价培美曲塞与顺铂静脉化疗同时联合苦参注射液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18例经胸腔镜确诊MPM合并胸腔积液患者,使用培美曲塞500mg/m2,d1;顺铂75mg/m2,d1-3;每21天重复。同时胸腔闭式引流术引流尽胸腔积液,苦参注射液40ml胸腔注入,每隔4天重复注射。结果:18例患者中,CR 4例,PR 8例,SD 4例,PD 2例。总有效率为66.67%,疾病控制率为88.89%,肿瘤进展时间为7.2个月,中位生存期为12.3个月,1年生存率为43.85%。16例(88.89%)胸腔积液得到控制。主要毒副反应为骨髓抑制、胃肠道反应、发热、胸痛及皮疹等,对症支持处理后均可恢复。结论:培美曲塞与顺铂静脉化疗同时苦参注射液胸腔灌注治疗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。     

普来乐联合顺铂治疗恶性胸膜间皮瘤的疗效观察

目的:观察普来乐联合顺铂治疗恶性胸膜间皮瘤的疗效。方法:选择36例恶性胸膜间皮瘤患者,男24例,女12例,年龄35-67岁,平均年龄46.3±2.6岁。给予普来乐联合顺铂进行治疗。结果:胸痛、呼吸困难等症状基本消失,胸水体征消失或明显减轻,全身状况好转;5例症状有所减轻,但仍有原不适主诉存在,全身状况所有不明显改善。36例病人完全缓解0例,部分缓解20例,无效16例,有效率为55.6%。结论:普来乐联合顺铂治疗恶性胸膜间皮瘤疗效显著。     

普来乐联合顺铂治疗恶性胸膜间皮瘤的疗效观察

目的：观察普来乐联合顺铂治疗恶性胸膜间皮瘤的疗效。方法：选择36例恶性胸膜间皮瘤患者,男24例,女12例,年龄35-67岁,平均年龄46.3±2.6岁。给予普来乐联合顺铂进行治疗。结果：胸痛、呼吸困难等症状基本消失,胸水体征消失或明显减轻,全身状况好转;5例症状有所减轻,但仍有原不适主诉存在,全身状况所有不明显改善。36例病人完全缓解0例,部分缓解20例,无效16例,有效率为55.6%。结论：普来乐联合顺铂治疗恶性胸膜间皮瘤疗效显著。     

Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma

BACKGROUND: Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. METHODS: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. RESULTS: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. CONCLUSIONS: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.     

Chemotherapy for malignant pleural mesothelioma: past results and recent developments

This review summarises the results of previously conducted clinical trials, and subsequently presents data arising from all phase II-III studies on chemotherapy of malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the antimetabolites, and in particular to pemetrexed that produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine-applied as a single agent or in combination with cisplatin-as well as vinorelbine appear to improve the quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. The publication of pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon establish a standard of care.     

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.     

Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.

BACKGROUND: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival. PATIENTS AND METHODS: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups. RESULTS: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72). CONCLUSIONS: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.     

Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m(2) in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero. RESULTS: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3-34.7]. In all, 29 (39%) (95% CI 28-48) patients reported stable disease. The median survival was estimated at 14 months. CONCLUSION: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.     

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.     

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。     

Management of malignant pleural mesothelioma

Malignant mesothelioma is a highly fatal malignancy that may become more prevalent in the Asia–Pacific region over the next decades. We review clinical aspects of this disease, including presentation, diagnosis, staging and management. A small proportion of patients will be suitable for aggressive trimodality therapy (extra‐pleural pneumonectomy, chemotherapy and radiotherapy) with the aim of cure or achieving prolonged palliation. However, most patients will present with advanced disease and so are only suitable for palliation. We review palliative therapy with an emphasis on the practical aspects of chemotherapy as well as palliative procedures such as pleurodesis. The future direction of clinical research in mesothelioma is discussed.     

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。     

吉西他滨联合多西他赛与培美曲塞联合顺铂治疗晚期恶性胸膜间皮瘤初步疗效对比

目的:观察吉西他滨联合多西他赛与培美曲塞联合顺铂化疗治疗恶性胸膜间皮瘤(MPM)的疗效及安全性.方法:回顾性分析我院初诊的MPM患者,GD方案(吉西他滨联合多西他赛)为试验组,PP方案(培美曲塞联合顺铂)为对照组,21天为一个周期,对比两组间患者的临床疗效及毒副反应.结果:30例MPM中,GD组和PP组中位化疗周期(4 vs 4.5个)、疾病控制率(DCR) (85.7％ vs 87.5％)、中位生存时间(mOS)(14 vs 15个月),两组差异均无统计学意义(P =0.086、P=0.982、P=0.564).GD组血液学毒性发生率高于PP组(64.3％ vs 18.8％),两组血液学毒性有差异(P=0.024);但GD组胃肠道反应发生率低于PP组,两组间无统计学差异(14.3％ vs 31.3％,P=0.399).结论:GD方案与PP方案在晚期MPM患者一线化疗中疗效相当;GD方案在血液学毒性高于PP方案,但多以Ⅰ-Ⅱ度骨髓抑制为主,安全性可接受.     

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Introduction

A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM.

Methods

MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival.

Results

Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66).

Conclusions

MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.     

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.     

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。     

CD74: a new prognostic factor for patients with malignant pleural mesothelioma

Background:

The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).

Methods:

Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.

Results:

Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.

Conclusions:

High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.     

吉西他滨联合洛铂二线治疗恶性胸膜间皮瘤的疗效观察

目的:比较吉西他滨联合洛铂及培美曲塞单药对一线化疗后复发的恶性胸膜间皮瘤的近期疗效、生活质量及不良反应。方法:将2013年6月至2016年12月确诊为恶性胸膜间皮瘤患者共48例,随机分为两组。治疗组23例:吉西他滨 1 000 mg/m2,第1、8天+洛铂 50 mg/m2,第2天。对照组25例:培美曲塞二钠500 mg/m2,第1天。治疗组和对照组均21天为一疗程,连续治疗六疗程。结果:治疗组有效率为30.43%,对照组有效率为24.00%,差异无统计学意义（P>0.05）。治疗组疾病控制率为65.22%,对照组疾病控制率为64.00%,差异无统计学意义（P>0.05）。治疗组患者生活质量改善率（69.57%）明显高于对照组（40.00%）,差异有统计学意义（P<0.05）。两组均未出现肝肾功能损害,心脏损害。两组不同程度的出现食欲下降、恶心、呕吐、白细胞减少等不良反应。两组间差异均未见统计学意义。结论:吉西他滨联合洛铂方案治疗一线化疗后复发的胸膜间皮瘤患者,取得与培美曲塞相似的疗效和可接受的不良反应,并可在一定程度上提高患者生活质量,可作为胸膜间皮瘤患者二线化疗的可选方案。