Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma

Background

CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin.

Methods

Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25 mg/m² IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months.

Results

65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS ≥ 4 mo; the median PFS was 5.1 mo (95% CI, 3.9, 6.5) vs 3.4 mo (2.5, 6.7). Median OS was 13.3 mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501.

Conclusions

While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for 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。     

Retreatment of recurrent malignant pleural mesothelioma with cisplatin and pemetrexed

Combination chemotherapy with cisplatin and pemetrexed is the most active first-line regimen for malignant pleural mesothelioma (MPM). However, no drugs have been approved for second-line treatment of MPM, with effective regimens remaining to be identified for patients in relapse. We have now evaluated the combination of cisplatin and pemetrexed for retreatment of patients with recurrent MPM. Four men with MPM, all of whom received initial treatment with cisplatin and pemetrexed, underwent retreatment with this drug combination. Two of the patients achieved an objective response to the first-line chemotherapy with no evidence of disease progression for 6.4 or 11.4 months, respectively. The other two patients had stable disease with a duration of 7.8 or 5.0 months, respectively. The two patients who showed an objective response to first-line chemotherapy showed a partial response to retreatment, with a time to progression of 5.0 or 8.2 months, whereas the other two patients had progressive disease with a time to progression of 1.0 or 1.4 months, respectively. Retreatment with cisplatin plus pemetrexed was generally well tolerated. Retreatment with cisplatin and pemetrexed is a potential therapeutic option for certain patients with recurrent epithelioid MPM, possibly including those who show tumor regression with a time to progression of 6 months or more after the initial chemotherapy. Further studies are warranted to evaluate the efficacy of such retreatment and to clarify the criteria for patient selection.     

Chemotherapy in malignant mesothelioma: a review

Summary This review of malignant mesothelioma focuses on the activity of single-agent and combination chemotherapy, a field in which research has thus far been rather unsystematic and sparse. Available results neither accede to any substantial drug activity nor justify the use of standard therapy. Furthermore, even when pooled most findings do not fulfil the basic criteria for a phase II trial. Prospective (multicenter) phase II trials are recommended for the identification of new agents that show antineoplastic activity in malignant mesothelioma. The use of computed tomography scans can assist in the prediction of the extent of disease both before and during treatment. Tumorbiological systems using mice xenografts or cell lines of human mesothelioma should be further developed so as to improve the screening of new agents exhibiting potential antineoplastic activity that is especially directed against mesothelioma.     

The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma

BackgroundPlatinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM.Patients and methodsIn total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms.ResultsGST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis.ConclusionsOur results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.     

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.     

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。     

Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: The ucla experience

From 1986 to 1993, 15 patients with malignant pleural mesothelioma were treated by pleurectomy/decortication and intrapleural cisplatin (100 mg/ m²) and cytosine arabinoside (1,200 mg). All patients were without known extrathoracic disease and had a mean age of 63.5 ± 7.9 years (range 51–78); 13 were male. Histologic subtype of disease were epithelial (47%), sarcomatoid (27%), and mixed-biphasic (27%). The major morbidity and mortality rates were 13% and 0%, respectively. The mean length of hospital stay was 6.5 ± 2.1 days. Postoperatively, adjuvant chemotherapy and radiation therapy were given to 46% and 73% of the patients respectively. Median survival from date of treatment was 11.5 months. Those patients with an epithelial histologic subtype experienced significantly improved survival compared to those of sarcomatoid subtype (P = 0.024). Whether adjuvant chemotherapy or radiation therapy were given had no significant effect on survival. These data suggest that although this treatment regimen can be administered with very limited morbidity and no mortality, the role of this approach in the treatment of malignant pleural mesothelioma appears limited and cannot currently be recommended. © 1995 Wiley-Liss, Inc.     

Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma

Introduction

The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0-1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM.

Methods

An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature.

Results

Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost.

Conclusion

Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.     

Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.

PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.     

Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines

Although cisplatin and pemetrexed are key drugs in the treatment of malignant pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance mechanisms in malignant pleural mesothelioma are not well understood. In the present study, the interaction of these 2 agents was determined by clonogenic assays followed by isobologram analysis of 4 human malignant pleural mesothelioma cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase mRNA expression was evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High thymidylate synthase expression did not correlate with natural pemetrexed resistance. Elevated thymidylate synthase expression correlated with acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural mesothelioma cell lines, suggesting the clinical relevance of their combination in chemotherapy. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. The information together with the experimental model presented here would be useful for further investigating therapeutic targets of malignant mesothelioma.     

Molecular biology of malignant mesothelioma: a review

Malignant mesothelioma (MM) is an uncommon tumor with high mortality and morbidity rates. It arises from mesothelial cells that line the pleural, pericardial, peritoneal, and testicular cavities. This is a disease with an indolent course because tumors arise 20 to 40 years after exposure to an inciting agent. Extensive research has shown that mesothelial cells are transformed into MM cells through various chromosomal and cellular pathway defects. These changes alter the normal cells' ability to survive, proliferate, and metastasize. This article discusses the alterations that occur in transforming normal mesothelial cells into MM. It also details some of the signal transduction pathways that seem to be important in MM with the potential for novel targeted therapeutics.     

Dramatic tumour response to pemetrexed single-agent in an elderly patient with malignant peritoneal mesothelioma: a case report

Background  

To date, there is no standard treatment for unresectable malignant peritoneal mesothelioma; either best supportive care or systemic chemotherapy with palliative intent are accepted options.     

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.     

Pemetrexed alone and in combination with platinum compounds in the management of malignant mesothelioma

Malignant pleural mesothelioma is an aggressive but rare malignancy with a dismal prognosis. It is traditionally resistant to chemotherapy. Antifolate agents have recently shown promising data in the treatment of this malignancy. Pemetrexed is a multitargeted antifolate inhibitor of thymidylate synthase and other folate-dependent enzymes that has emerged as one of the most active agents in this disease. Several phase I/II trials of pemetrexed as a single agent or in combination with a platinum drug have demonstrated considerable activity in mesothelioma. In a recently published phase III randomized study, pemetrexed/cisplatin showed a significant improvement in survival, response rate, and quality of life compared with single-agent cisplatin. In addition, several trials reported that folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed without affecting the efficacy of the drug.