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A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma

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Abstract

Purpose

Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged infusion plus cisplatin in patients with advanced pleural mesothelioma.

Methods

Patients with mesothelioma received gemcitabine (250 mg/m2) in a 6-h infusion plus cisplatin (35 mg/m2) on days 1 and 8 every three weeks. We used the modified response evaluation criteria in solid tumours. This study is registered in clinical trials (NCT01869023).

Results

We included 39 patients; 82.1 % were low risk according to the European Organisation for Research and Treatment of Cancer prognostic group. Partial response was observed in 53.8 % (21/39), stable disease in 33.3 % (13/39) and progression in 12.8 % (5/39). The median progression-free survival was 6.9 months (95 % CI 3.2–10.6 months), and the associated factors were the EORTC risk and histology. The median overall survival was 20.7 months (95 % CI 10.7–30.8 months). The functional, physical and emotional roles and dyspnoea, insomnia and pain symptom scales improved. The most commonly graded 3/4 side effects were neutropenia (24.4 %), lymphopenia (14.6 %), thrombocytopenia (14.7 %) and anaemia (12.2 %).

Conclusions

Low-dose, prolonged gemcitabine infusion plus cisplatin has acceptable toxicity and high efficacy with improved quality of life, representing an affordable regimen for the low-income population.

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References

  1. Selikoff IJ, Hammond EC, Seidman H (1980) Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 46(12):2736–2740

    Article  CAS  PubMed  Google Scholar 

  2. Tsao AS, Wistuba I, Roth JA et al (2009) Malig Pleur Mesothelioma J Clin Oncol 27(12):2081–2090. doi:10.1200/JCO.2008.19.8523

    Article  CAS  Google Scholar 

  3. Delgermaa V, Takahashi K, Park EK et al (2011) Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ 89(10):716–724. doi:10.2471/BLT.11.086678 724A–724C

    Article  PubMed Central  PubMed  Google Scholar 

  4. Aguilar-Madrid G, Robles-Pérez E, Juárez-Pérez CA et al (2010) Case-control study of pleural mesothelioma in workers with social security in Mexico. Am J Ind Med 53(3):241–251

    PubMed  Google Scholar 

  5. García-López MP, Barrera-Rodríguez R (2000) Malignant mesothelioma: clinical and radiological description of 45 cases with and without asbestos exposure. Salud Publica Mex 42(6):511–519

    Article  PubMed  Google Scholar 

  6. Park EK, Takahashi K, Hoshuyama T et al (2011) Global magnitude of reported and unreported mesothelioma. Environ Health Perspect 119(4):514–518. doi:10.1289/ehp.1002845

    Article  PubMed Central  PubMed  Google Scholar 

  7. NCCN Guidelines for Treatment of Malignat Pleural Mesothelioma (2013) IOP National Comprehensive Cancer Network Web. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed 23 Dec 2013

  8. Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21(14):2636–2644

    Article  CAS  PubMed  Google Scholar 

  9. van Meerbeeck JP, Gaafaar R, Manegold C et al (2005) Randomized phase III Study of Cisplatin With or Without Ralitrexed in Patients with Malignant Pleural Mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 23(28):2636–2644

    Google Scholar 

  10. Kelly RJ, Sharon E, Hassan R (2011) Chemotherapy and targeted therapies for unresectable malignant mesothelioma. Lung Cancer 73(3):256–263. doi:10.1016/j.lungcan.2011.04.014

    Article  PubMed Central  PubMed  Google Scholar 

  11. Nowak AK, Byrne MJ, Williamson R et al (2002) A multicenter phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 87(5):491–496

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Arrieta Ó, Medina LA, Estrada-Lobato E et al (2012) First-line chemotherapy with liposomal doxorubicin plus cisplatin for patients with advanced malignant pleural mesothelioma: phase II trial. Br J Cancer 106(6):1027–1032. doi:10.1038/bjc.2012.44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ralli M, Tourkantonis I, Makrilia N et al (2009) Docetaxel plus gemcitabine as first-line treatment in malignant pleural mesothelioma: a single institution phase II study. Anticancer Res 29(8):3441–3444

    CAS  PubMed  Google Scholar 

  14. Sørensen JB, Frank H, Palshof T (2008) Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleuralmesothelioma. Br J Cancer 99(1):44–50. doi:10.1038/sj.bjc.6604421

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Boons CC, VAN Tulder MW, Burgers JA et al (2013) The value of pemetrexed for the treatment of malignant pleural mesothelioma: a comprehensive review. Anticancer 33(9):3553–3561

    CAS  Google Scholar 

  16. Grossi F, Genova C, Gaitan ND et al (2013) Free drugs in clinical trials and their potential cost saving impact on the National Health Service: a retrospective cost analysis in Italy. Lung Cancer 81(2):236–240. doi:10.1016/j.lungcan.2013.03.021

    Article  PubMed  Google Scholar 

  17. Woods B, Paracha N, Scott DA et al (2012) Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma. Lung Cancer 75(2):261–267. doi:10.1016/j.lungcan.2011.07.011

    Article  PubMed  Google Scholar 

  18. Zwitter M, Kovac V, Smrdel U et al (2009) Gemcitabine in brief versus prolonged low-dose infusion, both combined with cisplatin, for advanced non-small cell lung cancer: a randomized phase II clinical trial. J Thorac Oncol 4(9):1148–1155. doi:10.1097/JTO.0b013e3181ae280f

    Article  PubMed  Google Scholar 

  19. Sezer O, Eucker J, Jakob C et al (2001) Achievement of complete remission in refractory Hodgkin’s disease with prolonged infusion of gemcitabine. Invest New Drugs 19(1):101–104

    Article  CAS  PubMed  Google Scholar 

  20. Brand R, Capadano M, Tempero M (2007) A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 15(4):331–341

    Article  Google Scholar 

  21. Akrivakis K, Schmid P, Flath B et al (1999) Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study. Anticancer Drugs 10(6):525–531

    Article  CAS  PubMed  Google Scholar 

  22. Cattel L, Airoldi M, Delprino L et al (2006) Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxycytidine-5′-triphosphate after prolonged infusion in patients affected by different solid tumors. Ann Oncol 17(Suppl 5):v142–v147

    Article  PubMed  Google Scholar 

  23. Maurel J, Zorrilla M, Puertolas T et al (2001) Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors. Anticancer Drugs 12(9):713–717

    Article  CAS  PubMed  Google Scholar 

  24. Anderson H, Thatcher N, Walling J et al (1996) A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. Br J Cancer 74(3):460–462

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Pollera CF, Ceribelli A, Crecco M et al (1997) Prolonged infusion gemcitabine: a clinical phase I study at low-(300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drugs 15(2):115–121

    Article  CAS  PubMed  Google Scholar 

  26. Touroutoglou N, Gravel D, Raber MN et al (1998) Clinical results of a pharmacodynamically based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9(9):1003–1008

    Article  CAS  PubMed  Google Scholar 

  27. Abbruzzese JL, Grunewald R, Weeks EA et al (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9(3):491–498

    CAS  PubMed  Google Scholar 

  28. Plunkett W, Huang P, Xu YZ et al (1995) Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22(4 Suppl 11):3–10

    CAS  PubMed  Google Scholar 

  29. Edwards JG, Abrams KR, Leverment JN et al (2000) Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 55(9):731–735

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Fennell DA, Parmar A, Shamash J et al (2005) Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J Clin Oncol 23(1):184–189

    Article  PubMed  Google Scholar 

  31. Arrieta Ó, Núñez-Valencia C, Reynoso-Erazo L et al (2012) Health-related quality of life in patients with lung cancer: validation of the Mexican–Spanish version and association with prognosis of the EORTC QLQ-LC13 questionnaire. Lung Cancer 77(1):205–211. doi:10.1016/j.lungcan.2012.02.005

    Article  PubMed  Google Scholar 

  32. Schouwink JH, Kool LS, Rutgers EJ et al (2003) The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 75(6):1715–1718

    Article  PubMed  Google Scholar 

  33. Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, de Klerk NH, Robinson BW et al (1999) Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 17(1):25–30

    CAS  PubMed  Google Scholar 

  34. van Haarst JM, Baas P, Manegold Ch et al (2002) Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 86(3):342–345

    Article  PubMed Central  PubMed  Google Scholar 

  35. Kalmadi SR, Rankin C, Kraut MJ et al (2008) Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810). Lung Cancer 60(2):259–263

    Article  PubMed Central  PubMed  Google Scholar 

  36. Castagneto B, Zai S, Dongiovanni D et al (2005) Cisplatin and gemcitabine in malignant pleural mesothelioma: a phase II study. Am J Clin Oncol 28(3):223–226

    Article  CAS  PubMed  Google Scholar 

  37. Favaretto AG, Aversa SM, Paccagnella A et al (2003) Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study. Cancer 97(11):2791–2797

    Article  CAS  PubMed  Google Scholar 

  38. Ceribelli A, Gridelli C, De Marinis F et al (2003) Prolonged gemcitabine infusion in advanced non-small cell lung cancer carcinoma: a randomized phase II study of two different schedules in combination with cisplatin. Cancer 98(2):337–343

    Article  CAS  PubMed  Google Scholar 

  39. de Perrot M, Feld R, Cho BC et al (2009) Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27(9):1413–1418. doi:10.1200/JCO.2008.17.5604

    Article  PubMed  CAS  Google Scholar 

  40. Lee CW, Murray N, Anderson H et al (2009) Outcomes with first-line platinum-based combination chemotherapy for malignant pleural mesothelioma: a review of practice in British Columbia. Lung Cancer 64(3):308–313. doi:10.1016/j.lungcan.2008.09.008

    Article  PubMed  Google Scholar 

  41. Kovac V, Zwitter M, Rajer M et al (2012) A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma. Anticancer Drugs 23(2):230–238. doi:10.1097/CAD.0b013e32834d7a1c

    Article  CAS  PubMed  Google Scholar 

  42. Rea F, Marulli G, Bortolotti L et al (2007) Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): feasibility and results. Lung Cancer 57(1):89–95

    Article  PubMed  Google Scholar 

  43. Bottomley A, Coens C, Efficace F et al (2007) Symptoms and patient-reported well-being: do they predict survival in malignant pleural mesothelioma? A prognostic factor analysis of EORTC-NCIC 08983: randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma. J Clin Oncol 25(36):5770–5776

    Article  CAS  PubMed  Google Scholar 

  44. Flores RM, Pass HI, Seshan VE et al (2008) Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 135(3):620–626. doi:10.1016/j.jtcvs.2007.10.054

    Article  PubMed  Google Scholar 

  45. Treasure T, Lang-Lazdunski L, Waller D et al (2011) Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 12(8):763–772. doi:10.1016/S1470-2045(11)70149-8

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The study protocol was approved by the local Institutional Scientific and Bioethics Committee (INCAN/CC/458/01-INCAN/CB/516/01/CB/656) in accordance with the ethical standards laid down in the 1,964 Declaration of Helsinki and its later amendments and was registered in clinical trials (NCT01869023).

Conflict of interest

All patients signed written informed consent. The authors do not have any conflict of interest to declare.

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Authors and Affiliations

  1. Thoracic Oncology Unit, Experimental Oncology Laboratory, Instituto Nacional de Cancerología (INCan), San Fernando # 22, Col. Sección XVI, Tlalpan, C.P. 14080, Mexico, D.F., Mexico

    Oscar Arrieta, Diego López-Macías, Víctor-Osvaldo Mendoza-García, Ludwing Bacon-Fonseca, Wendy Muñoz-Montaño, Eleazar-Omar Macedo-Pérez, Saé Muñiz-Hernández, Monika Blake-Cerda & José-Francisco Corona-Cruz

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  1. Oscar Arrieta
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  2. Diego López-Macías
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Correspondence to Oscar Arrieta.

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Arrieta, O., López-Macías, D., Mendoza-García, VO. et al. A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma. Cancer Chemother Pharmacol 73, 975–982 (2014). https://doi.org/10.1007/s00280-014-2429-5

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