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1.  Multicenter Phase II Trial of Neoadjuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignant Pleural Mesothelioma 
Journal of Clinical Oncology  2009;27(18):3007-3013.
Purpose
Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma.
Patients and Methods
Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second ≥ 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate.
Results
Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05).
Conclusion
This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival.
doi:10.1200/JCO.2008.20.3943
PMCID: PMC3646305  PMID: 19364962
2.  The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy 
British Journal of Cancer  2010;102(3):553-560.
Background:
The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRα).
Methods:
Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI50). FRα expression was determined by western blotting and that of FRα, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT–PCR. Immunohistochemistry for FRα was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed.
Results:
A wide range of GI50 values was obtained for the cell lines, H2452 cells being the most sensitive (GI50 22 nM) and RS5 cells having a GI50 value greater than 10 μM. No FRα protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRα was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRα and the outcome of pemetrexed treatment, and no significant difference between histological subtypes.
Conclusion:
Response to treatment with pemetrexed does not depend on the presence of FRα.
doi:10.1038/sj.bjc.6605501
PMCID: PMC2822938  PMID: 20051956
Folate receptor α; mesothelioma; pemetrexed; cell lines; immunohistochemistry
3.  Folylpoly-Glutamate Synthetase Expression is associated with Tumor Response and Outcome from Pemetrexed-based Chemotherapy in Malignant Pleural Mesothelioma 
Purpose
Pemetrexed-based chemotherapy represents the standard of care in firstline-treatment of advanced malignant pleural mesothelioma (MPM). However, there are no established predictors of clinical benefit. Pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, but the main target is thymidylate synthase (TS). Following cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-γ-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expression is associated with clinical outcome following pemetrexed-based chemotherapy.
Patients and Methods
Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79/84) or single-agent pemetrexed (5/84) as firstline treatment, were retrospectively analyzed. FPGS and TS protein expression was semiquantitatively assessed by using the H-Scoring system (range: 0–300). H-scores were correlated with radiological response according to modified RECIST, progression-free survival (PFS) and overall survival (OS).
Results
Median H-score of the entire cohort was 230 for FPGS (range: 100–300), and 210 for TS (range: 100–300). High FPGS protein expression was significantly associated with longer PFS (PCOX=0.0337), better objective tumor response (PR vs. SD + PD; PKW=0.003), and improved disease control rate (PR + SD vs. PD; PKW=0.0208), but not with OS. In addition, high TS protein expression was associated with PD under pemetrexed-based therapy (P=0.0383), and shorter OS (PCOX=0.0071), but no association with PFS was observed.
Conclusion
FPGS and TS expression were associated with clinical response and outcome to pemetrexed-based firstline chemotherapy in MPM. Prospective evaluation of FGPS and TS expression and their prognostic/predictive power in MPM patients is warranted.
doi:10.1097/JTO.0b013e318260deaa
PMCID: PMC3645940  PMID: 22895141
Malignant Pleural Mesothelioma; Biomarker; FPGS; TS; Pemetrexed
4.  Current therapies for malignant pleural mesothelioma 
Mesothelioma is a highly lethal tumor derived from mesothelial cells, and its global incidence is increasing because of widespread exposure of numerous individuals to asbestos in the last 50 years. Mesothelioma is largely untreatable with any of the therapeutic modalities. Recently, a novel multitargeted antifolate pemetrexed has shown promising activity against malignant pleural mesothelioma, producing response rates of up to 40% when used in combination with cisplatin. In a large phase III study, use of a combination of pemetrexed and cisplatin was associated with significantly improved survival time and with greater antitumor activity compared with cisplatin alone. This combination also gave a significant response rate of approximately 50% in patients with epithelioid malignant pleural mesothelioma. These clinical benefits of pemetrexed–cisplatin doublet have changed the perception of mesothelioma chemotherapy. Other combinations, including gemcitabine in combination with cisplatin, have also shown encouraging response rates. Prognosis depends on gender, clinical stage of the tumor, histological subtype, platelet count, leukocyte counts, and performance status. Radiotherapy can palliate mesothelioma patients with chest pain, and has been indicated to be of benefit for the prevention of malignant seeding along the tract of a chest tube or needle biopsy. Trimodality treatment using extrapleural pneumonectomy, radiation and chemotherapy has shown promising therapeutic value. The development of chemotherapeutic regimens and the favorable outcomes of trimodality have led to new combined modality trials. In Japan, multicenter national trials against mesothelioma will begin in the near future.
doi:10.1007/s12199-007-0016-7
PMCID: PMC2698270  PMID: 19568885
Asbestos; Extrapleural pneumonectomy; Mesothelioma; Pemetrexed
5.  Gemcitabine combined with oxaliplatin in pretreated patients with malignant pleural mesothelioma: an observational study 
Background
The aim of this study was to investigate the efficacy and safety of oxaliplatin ± gemcitabine in patients with diffuse malignant pleural mesothelioma (MPM) pretreated with pemetrexed.
Methods
The study enrolled consecutive patients with relapsed MPM, all of them pretreated with a platin-pemetrexed-based chemotherapy. Oxaliplatin 80 mg/m2 was administered as monotherapy or in combination with gemcitabine 1000 mg/m2 given on day 1 and 8. Cycles were repeated every 21 days. The primary endpoints were response rate and disease control rate. Secondary endpoints included overall survival (OS), time to tumour progression (TTP), progression-free survival (PFS), time to treatment failure (TTF), and toxicity.
Results
Between February 2005 and September 2007 29 patients (median age: 65.0 years, World Health Organisation (WHO) performance status: 0–3) were enrolled. The follow-up period encompassed 5.4 to 97.4 weeks (median: 24.3 weeks). Out of these 29 patients, 15 were treated in second, 10 in third, 3 in fourth and 1 in fifth line, respectively. The majority of the patients received the combination oxaliplatin and gemcitabine (n = 25 vs. 4; 86.2 vs. 13.8%).
The median overall survival (OS) was 71.7 weeks (30.6–243.3 weeks), whereas survival from the start of oxaliplatin/gemcitabine-treatment was 24.3 weeks (5.4–97.3 weeks). Median time to tumour progression (TTP) was 9.3 weeks (3.0–67.6 weeks).
Partial response (PR) was observed in 2 patients (6.9%), stable disease (SD) for at least three courses of treatment in 11 patients (37.9%). Thus, disease control rate was 44.8%, whereas 16 of 29 patients exhibited progressive disease (55.2%).
The toxicity profile was favourable, with no WHO grade 4-toxicities, only few dose-reductions were performed due to non-symptomatic haematotoxicities (neutropenia, thrombopenia). Mild WHO grade 2 neurotoxicity was seen in 6 patients.
Conclusion
Pemetrexed-pretreated patients with progressive MPM may benefit from a consecutive chemotherapy with oxaliplatin and gemcitabine without significant toxicity.
doi:10.1186/1745-6673-3-34
PMCID: PMC2621228  PMID: 19091133
6.  Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma 
Malignant pleural mesothelioma is a resistant form of lung cancer, and its incidence continues to rise in Europe and Australia. Until recently, chemotherapy had not been shown to be effective in the treatment of this slowly progressive disease. In 2004, the combination of pemetrexed and cisplatin was shown to induce high response rates in MPM. This article reviews the published literature describing the development and testing of this therapeutic combination in mesothelioma, and examines in detail the key phase III clinical trial that led to the approval of pemetrexed by the US FDA. Ongoing research will further define the role of pemetrexed plus cisplatin in the treatment of MPM.
PMCID: PMC2503655  PMID: 18728709
malignant pleural mesothelioma; mesothelioma; pemetrexed; cisplatin
7.  Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials 
British Journal of Cancer  2008;99(1):51-56.
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 ⩾70 years old. A total of 178 patients with an ECOG performance status of ⩽2 were included. Median age was 65 years (range 38–79), with 48 patients ⩾70 years (27%). Grade 3–4 haematological toxicity was slightly worse in ⩾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.
doi:10.1038/sj.bjc.6604442
PMCID: PMC2453025  PMID: 18542071
malignant pleural mesothelioma; elderly patients; chemotherapy; carboplatin; pemetrexed
8.  Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma 
BMC Cancer  2013;13:22.
Background
Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results.
Methods
Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m2+cisplatin 75 mg/m2 IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3–8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4–8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation.
Results
Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%).
Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended.
Conclusions
The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation.
Trial registration
Clinicaltrial.com registrationID #NCT00087698.
doi:10.1186/1471-2407-13-22
PMCID: PMC3722081  PMID: 23324131
Pemetrexed; Pleural mesothelioma; Chemotherapy; Surgery; Radiation
9.  The Evolution of Multimodality Therapy for Malignant Pleural Mesothelioma 
Opinion Statement
Malignant pleural mesothelioma (MPM) is a rare neoplasm of the pleural surfaces that has been associated with asbestos exposure. MPM generally spreads locally along the ipsilateral pleura, especially at presentation, with distant metastatic disease typically seen only in the later stages of the disease course. As such, surgical resection and other local therapies have long been pursued as a primary form of treatment. Surgical options include debulking of the pleura by pleurectomy/decortication (P/D), or a more aggressive extrapleural pneumonectomy (EPP) which also involves removal of the lung, diaphragm, and involved pericardium. Even after major resection, MPM almost always recurs locally and has a poor prognosis. As such, many groups have pursued multimodality therapy, treating resectable patients with extrapleural pneumonectomy (EPP), along with hemithoracic radiation to decrease the risk of local recurrence, and chemotherapy to decrease the risk of distant metastatic disease. However, EPP is associated with significant morbidity and mortality, and many patients are not candidates for EPP due to underlying comorbid medical conditions. Additionally, many patients are unable to tolerate complete courses of adjuvant therapy after EPP. A large, multi-center retrospective analysis comparing EPP to pleurectomy/decortication (P/D) demonstrated better outcomes among those who underwent P/D. One challenge associated with P/D has been the delivery or radiation to the removed pleura with an intact lung. Yet, advances in radiation technique have allowed the exploration of high-dose radiation therapy after P/D. The ideal timing of chemotherapy relative to surgery, and the role of intracavitary chemotherapy continue to be controversial issues. Clearly, MPM requires a multi-disciplinary approach and, due to the myriad of open questions, much effort continues to focus on identifying the optimal combination of surgery, chemotherapy, and radiation.
doi:10.1007/s11864-011-0146-4
PMCID: PMC3321839  PMID: 21404104
10.  Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma 
PLoS ONE  2012;7(8):e40521.
Background
Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.
Methodology and Principal Findings
Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden.
Conclusions
Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort.
doi:10.1371/journal.pone.0040521
PMCID: PMC3414492  PMID: 22905093
11.  Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies—results of a phase I dose-escalation study 
Investigational New Drugs  2013;31:1487-1498.
Summary
Objectives The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. Methods In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400–500 mg/m2 IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. Results Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m2 and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand–foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83 %) and leukopenia (83 %). Pharmacokinetic data revealed no clinically significant drug–drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60 %). Conclusions With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.
doi:10.1007/s10637-013-0010-4
PMCID: PMC3825543  PMID: 23963796
Solid tumors; Non-small cell lung cancer; Sunitinib; Pemetrexed; Carboplatin
12.  Treatment Failure after Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma 
Journal of Thoracic Disease  2009;1(1):23-28.
Background
Extrapleural pneumonectomy (EPP) has been used as a treatment option for selected patients with malignant pleural mesothelioma (MPM). The primary end-point of this study was disease-free survival (DFS). Prognostic indicators for local and overall DFS were statistically analyzed.
Methods
Between October 1994 to April 2008, 59 patients who had complete macroscopic cytoreduction after EPP formed the basis of this report. In recent years, selected patients received adjuvant radiotherapy and pemetrexed combined with cisplatin or carboplatin. The clinicopathologic data of all patients were prospectively collected in a computerized database. Statistical analysis was performed by using Kaplan-Meier method and compared using the log-rank test. Cox-regression model was used for multivariate analysis.
Results
The mean age at the time of EPP was 59 (S.D. = 8) years. Nineteen patients (32%) experienced perioperative complications. The median survival was 21 months (range 2 to 104). The local disease recurrence rate was 51%. The median local DFS was 22 months (0 to 73). The overall disease recurrence rate was 64%. The median overall DFS was 18 months (range 0 to 73). In multivariate analysis, epithelial subtype (p = 0.026) and adjuvant radiotherapy (p = 0.023) were independently associated with an improved local DFS. Adjuvant radiotherapy (p = 0.011) was also independently associated with an improved overall DFS.
Conclusions
This study demonstrated that that local disease failure was still a considerable clinical problem following complete EPP. The data also showed that patients with epithelial histology and receiving adjuvant radiotherapy were associated with an improved disease control.
PMCID: PMC3256490  PMID: 22262998
pleural mesothelioma; extrapleural pneumonectomy; radiotherapy
13.  Dramatic tumour response to pemetrexed single-agent in an elderly patient with malignant peritoneal mesothelioma: a case report 
BMC Cancer  2006;6:289.
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.
Case presentation
Here, we report the case of a 79-year old patient with malignant peritoneal mesothelioma who was treated with pemetrexed single-agent and obtained an impressive long-lasting response.
Conclusion
Single-agent pemetrexed is a treatment option for malignant peritoneal mesothelioma in selected elderly patients or in patients with unpaired performance status.
doi:10.1186/1471-2407-6-289
PMCID: PMC1764904  PMID: 17176466
14.  Late cutaneous metastases to the face from malignant pleural mesothelioma: A case report and review of the literature 
Background
Malignant Mesothelioma is a rare primary neoplasm affecting the serosal membranes. During its relative short course, this malignant neoplasm can give local and, rarely, distant haematogenous metastases in different organs. The reported metastatic sites include liver, lung, heart, brain, thyroid, adrenals, kidneys, pancreas, bone, soft tissue, skin and lymph nodes.
Case Presentation
We report a sixty one year-old man with a history of malignant pleural epithelioid mesothelioma treated with six cycles of Pemetrexed and Carboplatin completed 03/11/04 followed by radiotherapy to the drain site 250 Kv/TD20Gy/5F completed 13/12/2004. Then he developed multiple facial skin lesions 4 years later. These lesions were proved to be metastatic malignant sarcomatoid mesothelioma.
Conclusion
Mesothelioma metastases should be suspected in any known Mesothelioma patient with newly developed skin lesion.
doi:10.1186/1477-7819-7-84
PMCID: PMC2777157  PMID: 19900274
15.  CBDCA + Pemetrexed + Bevacizumab and Its Maintenance Chemotherapy in a Case of Solitary Breast Metastasis from a Lung Adenocarcinoma Resistant to Gefitinib 
Case Reports in Oncology  2012;5(3):546-553.
Based on the AVAPERL trial (36th ESMO 2011), CBDCA + pemetrexed + bevacizumab and its maintenance chemotherapy with pemetrexed + bevacizumab is a new promising regimen for the treatment of advanced non-small-cell lung adenocarcinoma. Herein, we report the rare case of a patient with solitary breast metastasis from a lung adenocarcinoma, which was effectively treated using CBDCA + pemetrexed + bevacizumab and its maintenance chemotherapy. A 57-year-old female was admitted to the hospital due to pleural effusion and cardiac tamponade caused by a lung adenocarcinoma possessing a mutation of the epidermal growth factor receptor (EGFR) gene (deletion of exon 19). The patient was treated by first-line chemotherapy (gefitinib 250 mg/body/day) which resulted in complete response. After 12 months, carcinoembryonic antigen was gradually increasing and she complained of a right breast mass. With a core-needle biopsy, the breast tumor was pathologically diagnosed as recurrence and solitary metastasis of a lung adenocarcinoma. Further study of the second mutation of EGFR revealed a T790M mutation. The patient was treated by second-line chemotherapy [CBDCA + pemetrexed + bevacizumab (AUC 6 + 500 mg/m2 + 15 mg/kg)] and its maintenance chemotherapy (pemetrexed + bevacizumab). The cases of patients with breast metastasis from other organs are very rare. Immunohistopathological analysis is very useful to diagnose whether the malignancy is primary or not. In the case of a breast tumor with present or previous malignancy, a metastatic breast tumor should be considered. Furthermore, the biopsy of the breast metastasis also revealed the second mutation of resistance to gefitinib, T790M. Of note, according to our case, CBDCA + pemetrexed + bevacizumab and its maintenance chemotherapy is feasible and well tolerated for breast metastasis from a lung adenocarcinoma which is resistant to gefitinib and possesses the T790M mutation in the EGFR gene.
doi:10.1159/000343678
PMCID: PMC3492973  PMID: 23139670
Solitary breast metastasis; Non-small-cell lung carcinoma; T790M; CBDCA + pemetrexed + bevacizumab; Maintenance therapy; Tyrosine kinase inhibitor resistance
16.  Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin 
British Journal of Cancer  2011;105(10):1542-1553.
Background:
Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin–pemetrexed in human MPM cell lines.
Methods:
We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation.
Results:
Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib–pemetrexed–carboplatin combination.
Conclusion:
Vandetanib markedly enhances pemetrexed–carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.
doi:10.1038/bjc.2011.400
PMCID: PMC3242521  PMID: 21970874
mesothelioma; targeted agents; EGFR pathway; thymidylate synthase; apoptosis; DNA repair genes
17.  Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience 
BMC Research Notes  2012;5:482.
Background
Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment.
Methods
We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment.
Results
Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively.
Conclusions
In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression.
doi:10.1186/1756-0500-5-482
PMCID: PMC3502102  PMID: 22943698
18.  Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer 
Cancer Biology & Therapy  2013;14(1):39-44.
Purpose: Pemetrexed is the only FDA approved treatment for mesothelioma and is a second line agent for treatment of non-small cell lung carcinoma (NSCLC). Pemetrexed is inhibited by folate and its analogs, which are components of many culture media, making it challenging to study pemetrexed in vitro. In order to accurately evaluate pemetrexed’s effects in vitro, the protocol for a standard chemosensitivity assay, the ChemoFx drug response marker, had to be modified.
Experimental Design: Novel rinse and media change steps were assessed and then added to the assay protocol in order to observe pemetrexed activity. The intraday and interday stability of pemetrexed were also established under the adapted protocol. Then, the modified protocol was used to examine pemetrexed in 65 ex vivo lung cancer specimens.
Results: Substituting 5% RPMI + EGF for BEGM allowed pemetrexed to exert its anticancer activity in the ChemoFx DRM. ChemoFx classified 6.2% of the lung specimens as responsive, 9.2% as intermediate responsive and 84.6% as non-responsive to pemetrexed.
Conclusions: Adapting the ChemoFx protocol allowed for the accurate evaluation of pemetrexed anticancer activity in ex vivo lung specimens. ChemoFx evaluation may provide an indication of a patient’s clinical response to the drug prior to pemetrexed treatment. Having this information when treatment options are being considered could avoid wasted time, unnecessary costs and needless side effects that are the result of an inappropriate chemotherapy regimen.
doi:10.4161/cbt.22622
PMCID: PMC3566050  PMID: 23114649
pemetrexed; ChemoFx; chemosensitivity; NSCLC; mesothelioma; individualized therapeutic response; chemotherapy
19.  Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia: Population-based survey of 444 patients 
Radiology and Oncology  2012;46(2):136-144.
Background
Malignant pleural mesothelioma is a rare tumour with increasing frequency throughout the world. Due to long latency after exposure to asbestos, restrictions in the production and use of asbestos have not yet alleviated the burden of mesothelioma. During the last decade, several trials confirmed the benefit of systemic treatment with drugs such as doublets with cisplatina and gemcitabine or pemetrexed for carefully selected patients in good performance status. The purpose of this survey was to assess the impact of systemic treatment for the whole national population of patients with mesothelioma.
Patients and methods.
A retrospective study included all patients in Slovenia with histologically confirmed diagnosis of malignant pleural mesothelioma in the period from 1974 till 2008. Data from the Cancer Registry of Slovenia were supplemented by review of clinical records of the Institute of Oncology in Ljubljana where virtually all non-surgical treatment for mesothelioma was performed. We analysed the incidence, treatment, and survival of patients treated in the era of infrequent chemotherapy (1974–2003, the first period) and after it (2004–2008, the second period).
Results
The survey included 444 patients, of whom 325 and 119 were diagnosed in the first and second period, respectively. Joinpoint regression analysis showed that after 1995 the trend in crude incidence rates increased more rapidly; the annual change was 0.03 per 100,000 per year before 1995 and 0.06 per 100,000 per year after. There was clear male predominance (70%) throughout the period covered by the survey. The proportion of patients above 65 years of age increased from 41.8% to 54.6% for the first and second period, respectively (p = 0.02). With a total of 52 (11.7%) operated patients, surgical treatment was rare and used only for selected patients with early disease and without comorbidity, leading to their relatively long median survival of 13.6 months. Chemotherapy was applied to 56 (17.2%) and to 96 (80.7%) patients during the first and second period, respectively. While a variety of older drugs were used in the first period, the most common regimen in the second period (applied to 91 patients) was doublet of low-dose gemcitabine in prolonged infusion and cisplatin. For the whole population of patients regardless the mode of treatment, median survival was 7.4 and 12.6 months (p-value = 0.037) for the first and second period, respectively.
Conclusions
Increasing incidence, male predominance and increased proportion of older patients confirm that the burden of mesothelioma persists in spite of a 15-years old ban in the production of asbestos. Modern chemotherapy, and in particular treatment with low-dose gemcitabine in prolonged infusion and cisplatin significantly prolonged median survival of patients with malignant pleural mesothelioma in Slovenia.
doi:10.2478/v10019-012-0032-0
PMCID: PMC3472938  PMID: 23077450
malignant pleural mesothelioma; incidence; survival; chemotherapy; gemcitabine in prolonged infusion
20.  Malignant pleural mesothelioma with long-term tumor disappearance of a local relapse after surgery: a case report 
Introduction
There have been few reports of spontaneous regression of malignant pleural mesothelioma, but the mechanism for this is unknown. We present a case report on a patient with malignant pleural mesothelioma showing apparent tumor disappearance in a local relapse after surgery.
Case presentation
A 73-year-old man presented with malignant pleural mesothelioma in the right thoracic cavity. A pleurectomy was performed, and as expected, the tumor locally relapsed with increasing chest pain. However, the symptoms suddenly improved while the tumor was apparently reduced, and spontaneous tumor regression was initially considered. The patient confessed that he had self-administered a mushroom extract with alternative parasympathetic nerve stimulation therapy thereafter. The complete disappearance of the tumor was clinically achieved during a 29-month follow-up with continuing self-treatment.
Conclusion
This is the first report describing a malignant pleural mesothelioma patient in Japan showing long-term complete disappearance of a local relapse after surgery. This event was a tumor regression possibly due to an immunological effect of combined complementary and alternative therapy.
doi:10.1186/1752-1947-3-6800
PMCID: PMC2726485  PMID: 19830126
21.  Giant malignant mesothelioma in the upper mediastinum: A case report 
Oncology Letters  2013;6(1):181-184.
Malignant mesothelioma in the mediastinum is rare and the majority of known cases have been reported as ‘localized mesothelioma’. The present study reports a case of an upper mediastinal tumor, which was diagnosed through thoracoscopic surgery and surgical biopsies of the mass. A computed tomography scan revealed a giant upper mediastinal tumor, adjacent to the aortic arch, trachea, superior vena cava and left pulmonary artery. The vessels in the mediastinum were compressed and were shifted to the lower right. The trachea became stenotic and a small amount of bilateral pleural effusion was observed. The mass was relatively well encapsulated. There was no pleural thickening or clearly swollen lymph nodes in the mediastinum. The histopathological and immunohistochemical examinations of the tumor verified the diagnosis of a malignant mesothelioma. The tumor was demonstrated to be derived from the mediastinal pleural mesothelium cells. The patient received pemetrexed disodium and cisplatin combination chemotherapy for four cycles. At present, the patient is undergoing follow-up.
doi:10.3892/ol.2013.1333
PMCID: PMC3742821  PMID: 23946800
malignant mesothelioma; upper mediastinal tumor; giant
22.  Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer: a case report 
Frontiers in Oncology  2012;2:152.
A 53-years-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement) in April 2009. First-line systemic treatment included six cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival.
doi:10.3389/fonc.2012.00152
PMCID: PMC3481158  PMID: 23112957
vaccines; lung cancer; immunotherapy; chemotherapy; concurrent review
23.  Adjuvant Bidirectional Chemotherapy with Intraperitoneal Pemetrexed Combined with Intravenous Cisplatin for Diffuse Malignant Peritoneal Mesothelioma 
Cytoreductive surgery (CRS) with heated intraoperative intraperitoneal chemotherapy (HIPEC) has emerged as optimal treatment for diffuse malignant peritoneal mesothelioma (DMPM) showing median survivals of 36–92 months. However, recurrences occur frequently even in patients undergoing optimal cytreduction and are often confined to the abdomen. We initiated a Phase II study of adjuvant intraperitoneal pemetrexed combined with intravenous cisplatin for patients undergoing CRS and HIPEC for DMPM. The treatment consisted of pemetrexed 500 mg/m2 intraperitoneally and cisplatin 50 mg/m2 intravenously given simultaneously on day 1 of every 21 day cycle for 6 cycles. The primary endpoint of the study was treatment related toxicity. From July 2007 until July 2009 ten patients were enrolled. Nine of 10 completed all 6 cycles of adjuvant treatment per protocol. The most common toxicities were fatigue, nausea and abdominal pain grade 1 or 2. There was one grade 3 toxicity consisting of a catheter infection. The median survival for all 10 patients was 33.5 months. Pharmacokinetic analysis of intraperitoneal pemetrexed showed a peritoneal to plasma area under the curve ratio of 70. Our study shows that adjuvant intravenous cisplatin and intraperitoneal pemetrexed can be used following CRS and HIPEC for DMPM with low morbidity.
doi:10.1155/2012/890450
PMCID: PMC3423889  PMID: 22927839
24.  A case report of an extremely rare and aggressive tumor: primary malignant pericardial mesothelioma 
Rare Tumors  2012;4(2):e21.
Primary pericardial malignant mesothelioma (PMPM) is extremely rare with an incidence less than 0.0022%. It comprises 0.7% of all mesothelioma cases. To date, approximately 350 cases of pericardial mesothelioma have been reported in the literature. Its typical presentation is insidious, with nonspecific signs and symptoms, and usually results in constrictive pericarditis, cardiac tamponade and congestive heart failure either by a serous effusion or by direct tumorous constriction of the heart. With the exception of several case reports, the outcome is uniformly fatal, and patients typically die within six months of diagnosis. Here we report a 72-year-old Cauca -sian male with persistent pericardial and pleural effusion. He was diagnosed with PMPM after pericardectomy. He had only one cycle of chemotherapy with cisplatin and pemetrexed. He developed acute kidney injury as result of chemotherapy. He died 1 month after diagnosis and 6 months after the first symptoms.
doi:10.4081/rt.2012.e21
PMCID: PMC3401149  PMID: 22826778
medicine; oncology; primary pericardical malignant mesothelioma.
25.  Pleural Mesothelioma Presenting as Periumbilical Metastasis: The First Clinical Documentation 
Introduction. Pleural mesothelioma with metastasis to the subcutaneous tissue of the abdominal wall at first diagnosis and without penetration into the peritoneum is an extremely rare clinical presentation. Methods. Patients with pleural mesothelioma have low survival rate. Usually, the disease at presentation is confined to its site of origin (most often the pleural cavity). A 55-year-old man was referred to our center due to increasing dyspnea and a painful periumbilical mass in the anterior abdominal wall. CT scan revealed both advanced mesothelioma of the pleura and a tumor mass confined to the subcutaneous fatty tissue without penetration through the peritoneum. Results. Video-assisted thoracoscopy confirmed the diagnosis of epithelioid pleural mesothelioma, which was also confirmed by a biopsy of the periumbilical mass. Systemic chemotherapy with cisplatin and pemetrexed was initiated. Under the ongoing systemic chemotherapy, the evaluation revealed partial remission of pleura mesothelioma and its subcutaneous manifestation of the abdominal wall. Conclusion. Mesothelioma of the pleura with a simultaneous metastasis to the subcutaneous fatty tissue of the abdominal wall at presentation without penetration of peritoneum is a rare clinical presentation of mesothelioma disease. The knowledge of its natural history is very limited. This is the first ever clinical documentation of a patient with pleura mesothelioma and simultaneous subcutaneous manifestation of abdominal wall.
doi:10.1155/2013/198729
PMCID: PMC3652096  PMID: 23691382

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