Xanthopoulos A, Bauer TT, Blum TG, Kollmeier J, Schönfeld N, Serke M.

Respiratory Diseases Clinic Heckeshorn, Department of Pneumology, HELIOS Klinikum Emil von Behring, Berlin, Germany. torsten.bauer@helios-kliniken.de.

Abstract

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.

van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA.

National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. robbertvdm@gmail.com

Abstract

Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

Keywords: Tumor immunity – Regulatory CD4+ T cells – Chemotherapy – Mesothelioma – Gemcitabine – Cyclophosphamide

Lee CW, Murray N, Anderson H, Rao SC, Bishop W.

BC Cancer Agency – Fraser Valley Centre, 13750 96th Avenue, Surrey, British Columbia, Canada V3V 1Z2. clee@bccancer.bc.ca

Abstract

Cisplatin plus pemetrexed has been standard systemic therapy for malignant pleural mesothelioma (MPM) since the landmark randomized trial reported in 2003. However, the combination of cisplatin and gemcitabine was incorporated into clinical practice following publication of promising phase II trial results in 1999. The impact of these platinum-based regimens is assessed in this review of practice in the province of British Columbia. All cases of MPM diagnosed from 1999 to 2005 were identified in a provincial registry using ICD-O codes. The clinical records of individuals referred to the BC Cancer Agency were reviewed, and those treated with a platinum analog plus gemcitabine or pemetrexed as first-line therapy were included in survival analyses. During the selected period, 81 patients were treated first-line with a platinum analog plus gemcitabine (n=40) or pemetrexed (n=41). Characteristics of the entire cohort include: age at diagnosis, mean 65 years (median 66, range 43-84); gender, male 70 (86%); laterality of disease, right-sided 51 (63%); histology, epithelioid or not otherwise specified 69 (85%). Median survival was 10 months (95% confidence interval, 7.7-12.3), with 1- and 2-year survival rates 0.42 and 0.21, respectively. Survival did not appear to be influenced by the chemotherapy agent used. Survival outcomes with chemotherapy for MPM in the province are comparable to what is reported in the literature. No difference is seen combining platinum analogs with gemcitabine or pemetrexed. Platinum-based doublets might represent a therapeutic ceiling for cytotoxic chemotherapy in MPM.

Hillerdal G, Sorensen JB, Sundström S, Riska H, Vikström A, Hjerpe A.

Department of Lung Medicine and Allergology, Karolinska University Hospital, Solna, Stockholm, Sweden. gunnar.hillerdal@karolinska.se

Abstract

Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination of liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study.

Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-up, but all the others were followed for at least 4 years or until death.

Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months.

Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on radical surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.

Ryad AY, Mostafa E, Salem DA, Al-Adwy ER, Margerges M.

The Departments of Radiation Oncology&Nuclear Medicine, Ain Shams University.

Abstract

Purpose: To evaluate the efficacy, safety, and clinical benefit of combined gemcitabine and carboplatin in patients with previously untreated malignant pleural mesothelioma (MPM).

Patients and Methods: This prospective phase II study was performed on 42 eligible patients with histologically or cytologically proven MPM presenting to Ain Shams University hospitals and Sohag Cancer Center between January 2002 and April 2006. They were assigned to receive combined gemcitabine (1250mg/m2) on days, 1 and 8 and carboplatin (AUC 6) on day 1. The regimen was repeated every 21 days. The treatment continued until disease progression or intolerable drug toxicity.

Results: The patients received a total of 227 cycles of chemotherapy (median 5.4 cycles and range from 2 to 9 cycles). The chemotherapy was generally well tolerated. Neutropenia, thrombocytopenia and anemia were the most severe (Grade 3 or 4) toxicities recorded during therapy and were reported in (14%), (9.5%), and (9.5%), respectively. Twelve patients (29%) achieved partial response, 18 patients (42%) had stable disease and the disease progressed in the remaining 12 patients (29%). The median follow-up duration was 11 months (range 5 from 20 months). The overall survival (OS) and progression free survival (PFS) at one year was 44.5% and 33.2%, respectively. The median survival and time to disease progression were 11 months and 8.5 months respectively. Of 32 patients assessed for clinical benefit, 20 patients (62.5%) were considered clinical benefit responders.

Conclusion: The combination of gemcitabine and carboplatin is a safe and tolerable treatment with reasonable response rate, OS, and PFS compared with the historical phase II single agents and combined chemotherapy studies in patients with MPM.

Keywords: Mesothelioma , Gemcitbine , Carboplatin.

Felip E, Rosell R.

Vall d’Hebron University Hospital Barcelona, Spain.

Abstract

NSCLC accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced, unresectable disease, which remains incurable. In advanced disease, chemotherapy with platinum (cisplatin or carboplatin) in combination with a third-generation cytotoxic drug (vinorelbine, gemcitabine, paclitaxel, or docetaxel) can provide a modest improvement in survival without impairing quality of life. In chemotherapy-naïve, advanced, non-squamous NSCLC patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. Response rates of 20%-40% can now be expected, with a median survival of 8-11 months and a 1-year survival rate of 30%-40%. In second-line treatment, docetaxel has shown superiority to best supportive care in terms of survival and quality of life. A pooled analysis comparing docetaxel administered weekly versus 3-weekly found similar survival rates between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in several tumors, including mesothelioma and NSCLC. In a phase III trial, second-line treatment with pemetrexed demonstrated overall survival comparable to docetaxel, with a more manageable toxicity profile.

Keywords: pemetrexed, second-line therapy, NSCLC

Kindler HL.

Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu

Abstract

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients
with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival.
The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed
to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

Simon GR, Verschraegen CF, Jänne PA, Langer CJ, Dowlati A, Gadgeel SM, Kelly K, Kalemkerian GP, Traynor AM, Peng G, Gill J, Obasaju CK, Kindler HL.

Thoracic Oncology Program and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, MRC-4W, 12902 Magnolia Drive, Tampa, FL 33612-9497, USA. george.simon@moffitt.org

Abstract

Purpose: Pemetrexed in combination with cisplatin is approved for the treatment of pleural mesothelioma and is active in malignant peritoneal mesothelioma (MPeM). Pemetrexed and gemcitabine are synergistic in preclinical models, but the activity of this combination in MPeM is unknown. This clinical study assessed safety and efficacy of pemetrexed plus gemcitabine in chemotherapy-naïve patients with MPeM.

Patients and Methods: Treatment consisted of gemcitabine 1,250 mg/m2 on days 1 and 8, and pemetrexed 500 mg/m2 on day 8, administered immediately before gemcitabine. Treatment was repeated every 21 days for six cycles or until disease progression. All patients received folic acid, vitamin B12, and dexamethasone supplementation. End points included tumor response, toxicity, time to disease progression (TTPD), and overall survival (OS). Disease control rate (DCR) was also calculated.

Results: Twenty patients were enrolled between December 2002 and May 2004. The confirmed response rate was 15% (95% CI, 3.2% to 37.9%), with three patients experiencing a partial response. The DCR was 50% (95% CI, 27.2% to 72.8%). The most common grade 3 to 4 nonhematologic toxicities included fatigue (20%), constipation (10%), vomiting (10%), and dehydration (10%). Hematologic toxicities included grade 3 to 4 neutropenia (60%) and febrile neutropenia (10%). One patient death was attributed to treatment. Median TTPD and OS times were 10.4 months and 26.8 months, respectively.

Conclusion: The combination of pemetrexed plus gemcitabine was active in patients with MPeM with a notably high incidence of neutropenia. Median TTPD and OS seem promising. This regimen may provide an alternative to standard therapies, especially for patients who cannot tolerate a platinum-based regimen.

Nagai S, Takenaka K, Sonobe M, Wada H, Tanaka F.

Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Abstract

Background: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299.

Methods: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction.

Results: MTA showed potent cytotoxicity against 211H cells (IC₅₀

Conclusion: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM.

Keywords: Pemetrexed, Gemcitabine, Pleural mesothelioma, Lung cancer, Combination chemotherapy

Karpathiou G, Argiana E, Koutsopoulos A, Froudarakis ME.

Department of Pneumonology, Medical School Democritus University of Thrace, Alexandroupolis, Greece.

Abstract

We report the case of a 56-year-old patient with malignant pleural mesothelioma of epithelial type, who responded to second-line chemotherapy with lipoplatin plus gemcitabine. Diagnosis and staging of the disease was done by medical thoracoscopy with biopsies of the right pleura in December 2003, when he was treated with talc pleurodesis. Eighteen months later, he presented with pleural effusion of the left side and underwent first-line chemotherapy with cisplatin plus vinorelbine. After 8 cycles, the patient presented renal toxicity limiting further cisplatinum chemotherapy and disease progression with peritoneal invasion of the tumor and ascites. Treatment with lipoplatin-gemcitabine was decided on in November 2006, and the patient showed important improvement in the clinical status and peritoneal effusion. He survived for 36 weeks, with symptom-free survival of 34 weeks.

Keywords: Lipoplatin, Gemcitabine, Mesothelioma, Second-line chemotherapy, Thoracoscopy, Cisplatin, Vinorelbine