Systemtherapie des malignen Pleuramesothelioms: Gibt es Fortschritte?

Zusammenfassung

Die Chemotherapie des malignen Pleuramesothelioms ist von großer Bedeutung, da die meisten Patienten in einem fortgeschrittenen, inoperablem Stadium diagnostiziert werden. Die Validierung der Effektivität der Chemotherapie war aufgrund geringer Fallzahlen und unscharfer Bewertungskriterien in den letzten 20 Jahren nur eingeschränkt möglich, wobei schon früh eine symptomatische palliative Wirksamkeit gezeigt werden konnte. Nach Einführung der modernen Antifolate in die Therapie des Pleuramesothelioms und nach Etablierung von standardisierten Ansprechkriterien, konnte in randomisierten Phase-III-Studien eine signifikante Verlängerung der Überlebenszeit durch eine kombinierte Chemotherapie belegt werden, wobei die Kombination von Cisplatin und Pemetrexed der derzeitige Standard in der Chemotherapie ist. Neben der Erstlinientherapie gibt es auch Hinweise auf eine Aktivität der Chemotherapie beim vorbehandelten Patienten. Trotz wiederholter präklinischer Hinweise auf eine relevante prognostische Bedeutung verschiedener Zielstrukturen in der intra- und interzellulären Signaltransduktion wurde bisher keine signifikante Aktivität von zielgerichteten Therapien beim Pleuramesotheliom beobachtet.

Abstract

Chemotherapy of malignant mesothelioma is of great importance because most patients with malignant pleural mesothelioma are diagnosed for the first time with widespread or advanced disease. Due to the small number of patients in clinical trials and due to difficulties in tumour assessment in the last 20 years, validation criteria for efficacy could only be defined with major limitations. After the introduction of modern antifolates in the chemotherapy for malignant mesothelioma and after the establishment of standardised response criteria, a significant prolongation of survival time by combination chemotherapy was shown in two randomised phase III trials. The combination of pemetrexed and cisplatin is the current standard of chemotherapy in malignant mesothelioma. Besides first-line therapy, there are also data to support the efficacy of chemotherapy in pretreated patients. In spite of the various results of preclinical trials which support the prognostic significance of certain targeted structures of intra- and intercellular signal transduction, no relevant efficacy could be shown for targeted therapies in mesothelioma up to now.

Schlüsselwörter

malignes Pleuramesotheliom - Chemotherapie - Pemetrexed - prognostische Gruppen - Zweitlinientherapie

Key words

malignant pleural mesothelioma - chemotherapy - pemetrexed - prognostic groups - second-line therapy

Literatur

• 1 Adjei A A. Pemetrexed: a novel multitargeted antifolate agent.  Expert Rev Anticancer Ther. 2003;  3 145-156
• 2 Antman K H. Natural history and epidemiology of malignant mesothelioma.  Chest. 1993;  103 (Suppl 4) 373S-376S
• 3 Boutin C, Schlesser M, Freneay C et al. Malignant pleural mesothelioma.  Eur Respir J. 1998;  12 972-981
• 4 Curran D, Sahmoud T, Therasse P et al. Prognostic factors in patients with pleural mesothelioma: the European Organizations for Research and Treatment of Cancer experience.  J Clin Oncol. 1998;  16 145-152
• 5 Ellis P, Davies A M, Evans W K et al. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline.  J Thorac Oncol. 2006;  1 591-601
• 6 Fennell D A, Parmar A, Shamash J et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials.  J Clin Oncol. 2005;  23 184-189
• 7 Garland L, Rankin C, Scott K et al. Molecular correlates of the EGFR signaling pathway in associations with SCOG S0218: a Phase II study of oral EGFR tyrosine kinase inhibitor OSI-774 in patients with malignant pleural mesothelioma.  Proc Am Soc Clin Oncol. 2004;  Abstr. 3007
• 8 Govindan R, Kratzke R A, Herndon J E Cancer and Leukemia Group B (CALGB 30101) et al. Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B.  Clin Cancer Res. 2005;  15 2300-2304
• 9 Green J, Dundar Y, Dodd S et al. Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma.  Cochrane Database Syst Rev. 2007;  24 CD005574
• 10 Halme M, Knuutila A, Vehmas T et al. High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma.  Br J Cancer. 1999;  80 1781-1785
• 11 Herndon J E, Green M R, Chahinian A P et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B.  Chest. 1998;  113 723-731
• 12 Hollen P J, Gralla R J, Liepa A M et al. Adapting the Lung Cancer Symptom Scale (LCSS) to mesothelioma: using the LCSS-Meso conceptual model for validation.  Cancer. 2004;  101 587-595
• 13 Hughes A, Calvert P, Azzabi A et al. Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma.  J Clin Oncol. 2002;  20 3533-3544
• 14 Jassem J, Ramlau R, Santoro A et al. A randomized phase III trial comparing Pemetrexed plus best supportive care (BSC) vs BSC in previously treated patients with advanced malignant pleural mesothelioma.  Ann Oncol. 2006;  17 (Suppl 9) ,  Abstr. 7150
• 15 Karrison T, Kindler H L, Gandara D R et al. Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine / cisplatin (GC) plus bevacizumab or placebo in patients with malignant mesothelioma.  Proc Am Soc Clin Oncol. 2007;  Abstr. 7526
• 16 Kindler H L, Belani C P, Herndon II J E et al. Edatrexate with or without leucovorin rescue for malignant mesothelioma. Sequential Phase II trials by the Cancer and Leukemia Group B.  Cancer. 1999;  86 1985-1991
• 17 Paloetti P, Pistolese M, Rusthoven J J et al. Correlation of pulmonary function tests with best tumor response status: results from the Phase III study of pemetrexed + cisplatin versus cisplatin in malignant pleural mesothelioma.  Proc Am Soc Clin Oncol. 2003;  Abstr. 24 961
• 18 Pinto C, Marino A, Guaraldi M et al. Combination chemotherapy with mitoxantrone, methotrexate and mitomycin in malignant pleural mesothelioma: a phase II study.  Am J Clin Oncol. 2001;  24 143-147
• 19 Rusch V W, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma.  Thorac Cardiovasc Surg. 1996;  111 815-825
• 20 Santoro A, O'Brien M, Stahel R et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: Results of the International Expanded Access Program.  Proc Am Soc Clin Oncol. 2007;  Abstr. 7562
• 21 Scagliotti G V, Shin D M, Kindler H L et al. Phase II study of pemetrexed with and without folic acid and vitamin B₁₂ as frontline therapy in malignant pleural mesothelioma.  J Clin Oncol. 2003;  21 1556-1561
• 22 Soerensen J B, Sundstroem S, Perell K et al. Pemetrexed as second-line treatment in malignant pleural mesothelioma after platinum-based first-line treatment.  J Thorac Oncol. 2007;  2 147-152
• 23 Solheim O P, Saeter G, Finnanger A M et al. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study.  Br J Cancer. 1992;  65 956-960
• 24 Taylor P, Pawel J von, Castagneto B et al. Open-label study of pemetrexed alone for chemonaive patients and pre-treated patients with malignant pleural mesothelioma: Outcomes of the International Expanded Access Program.  Proc Am Soc Clin Oncol. 2007;  Abstr. 7709
• 25 Therasse P, Arbuck S G, Eisenhauer E A et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.  J Natl Cancer Inst. 2000;  92 205-216
• 26 Thodtmann R, Depenbrock H, Dumez H et al. Clinical and pharmacokinetic phase I study of multitargeted antifolate in comination with cisplatin.  J Clin Oncol. 1999;  17 3009-3016
• 27 Van Meerbeck J P, Gaafar R, Manegold C European Organisation for Research and Treatment of Cancer Lung Cancer Group: National Cancer Institute of Canada et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and National Cancer Institute of Canada.  J Clin Oncol. 2005;  23 6881-6889
• 28 Vogelzang N J, Weissman L B, Herndon II J E et al. Trimetrexate in malignant mesothelioma: a Cancer and Leukemia Group B Phase II study.  J Clin Oncol. 1994;  12 1436-1442
• 29 Vogelzang N J, Rusthoven J J, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.  J Clin Oncol. 2003;  21 2636-2644