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Chemotherapy for Malignant Pleural Mesothelioma: Past, Present and Future

  • Pleural Diseases and Mesothelioma (G Lee, Section Edtior)
  • Published:
Current Pulmonology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This paper aims to propose an update on therapeutic medical options for malignant pleural mesothelioma (MPM).

Recent Findings

For 13 years, the standard of care in MPM patients has been cisplatin/pemetrexed chemotherapy. Recently, the Cis/Pem/bevacizumab triplet emerged as a new option for MPM patients eligible for bevacizumab, and not as a candidate for multimodality therapy trials, as validated by the last NCCN and French guidelines. Immunotherapy is also emerging as a promising option on its own or in combination with first-line Cis/Pem, or even as a valuable alternative to chemotherapy, radical surgery, and multimodality strategies.

Summary

Targeted therapies and immunotherapy are new promising treatments in MPM as single agents or in combination with chemotherapy. However, the key challenge remains to find reliable predictive biomarkers for these innovative, exciting, and expensive treatments to select the best patients for each strategy. After years of nihilism and negative trials, numerous therapeutic strategies can now be offered to mesothelioma patients and the future looks brighter.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366(9483):397–408.

    Article  CAS  Google Scholar 

  2. Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010;35:479–95.

    Article  CAS  Google Scholar 

  3. van Zandwijk N, Clarke C, Henderson D, Musk AW, Fong K, Nowak A, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis. 2013;5(6):E254–307.

    PubMed  PubMed Central  Google Scholar 

  4. Baas P, Fennell D, Kerr KM, Van Schil PE, Haas RL, Peters S, ESMO Guidelines Committee. Malignant pleural mesothelioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v31–9.

    Article  CAS  Google Scholar 

  5. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–44.

    Article  CAS  Google Scholar 

  6. Santoro A, O’Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008;3:756–63.

    Article  Google Scholar 

  7. Zucali PA, Simonelli M, Michetti G, Tiseo M, Ceresoli GL, Collovà E, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer. 2012;75:360–7.

    Article  CAS  Google Scholar 

  8. Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer. 2014;84(3):271–4.

    Article  Google Scholar 

  9. Scherpereel T, Berghmans JJ, Lafitte B, Colinet M, Richez Y, Bonduelle AP, Meert X, Dhalluin N, Leclercq M, Paesmans L, Willems JP. Sculier for the European Lung Cancer Working Party (ELCWP). Valproate-doxorubicin: effective therapy for progressing mesothelioma. A phase II study. Eur Respir J. 2011;37:129–35.

    Article  CAS  Google Scholar 

  10. Jänne PA, Wozniak AJ, Belani CP, Keohan M-L, Ross HJ, Polikoff JA, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program. J Thorac Oncol. 2006;1:506–12.

    Article  Google Scholar 

  11. Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol. 2008;26:1698–704.

    Article  CAS  Google Scholar 

  12. • Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, Gnad F, Nguyen TT, Jaiswal BS, Chirieac LR, Sciaranghella D, Dao N, Gustafson CE, Munir KJ, Hackney JA, Chaudhuri A, Gupta R, Guillory J, Toy K, Ha C, Chen YJ, Stinson J, Chaudhuri S, Zhang N, Wu TD, Sugarbaker DJ, de Sauvage FJ, Richards WG, Seshagiri S. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–16. This article reports the most extensive and updated analysis of MPM genomics in a large series of well-characterized patients, providing new directions for personalized treatment in MPM.

    Article  CAS  Google Scholar 

  13. Buikhuisen WA, Burgers JA, Vincent AD, et al. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomized phase 3 study. Lancet Oncol. 2013;14(6):543–51.

    Article  CAS  Google Scholar 

  14. Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol. 2012;30:2509–15.

    Article  CAS  Google Scholar 

  15. Ceresoli GL, Zucali PA, Mencoboni M, Botta M, Grossi F, Cortinovis D, Zilembo N, Ripa C, Tiseo M, Favaretto AG, Soto-Parra H, De Vincenzo F, Bruzzone A, Lorenzi E, Gianoncelli L, Ercoli B, Giordano L, Santoro A. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer. 2013;109(3):552–8.

    Article  CAS  Google Scholar 

  16. Dowell JE, Dunphy FR, Taub RN, Gerber DE, Ngov L, Yan J, Xie Y, Kindler HL. A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma. Lung Cancer. 2012;77(3):567–71.

    Article  Google Scholar 

  17. •• Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A, French Cooperative Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma avastin cisplatin pemetrexed study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405–14. This study is the first positive, large, randomized controlled trial in MPM for 13 years, suggesting a new standard medical treatment in these patients.

    Article  CAS  Google Scholar 

  18. Buikhuisen WA, Scharpfenecker M, Griffioen AW, Korse CM, van Tinteren H, Baas P. A randomized phase II study adding axitinib to pemetrexed-cisplatin in patients with malignant pleural mesothelioma: a single-center trial combining clinical and translational outcomes. J Thorac Oncol. 2016;11(5):758–68.

    Article  Google Scholar 

  19. Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, Weaver DT, Menges C, Padval M, McClatchey AI, Xu Q, Testa JR, Pachter JA. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014;6(237):237.

    Article  Google Scholar 

  20. Szlosarek PW, Steele JP, Nolan L, Gilligan D, Taylor P, Spicer J, Lind M, Mitra S, Shamash J, Phillips MM, Luong P, Payne S, Hillman P, Ellis S, Szyszko T, Dancey G, Butcher L, Beck S, Avril NE, Thomson J, Johnston A, Tomsa M, Lawrence C, Schmid P, Crook T, Wu BW, Bomalaski JS, Lemoine N, Sheaff MT, Rudd RM, Fennell D, Hackshaw A. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 2017; 3(1): 58-66.

    Article  Google Scholar 

  21. Szlosarek P, Spicer J, Phillips M, Steele J, Rush H, Diaz M, Barba A, Johnston A, Khadeir R, Sheaff M, Bomalaski J, Pacey S. Phase 1 dose expansion experience of ADI-PEG20, pemetrexed and cisplatin in patients with malignant mesothelioma (TRAP study). 13th International Conference of the International Mesothelioma Interest Group. Birmingham: iMig; 2016. p. 47. abstracts book; MS10.02

    Google Scholar 

  22. Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Luk H, Baumann F, Zhang YA, Gazdar A, Kanodia S, Tiirikainen M, Flores E, Gaudino G, Becich MJ, Pass HI, Yang H, Carbone M. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol. 2015;10(4):565–76.

    Article  CAS  Google Scholar 

  23. Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, Sementino E, Tan Y, Menges CW, Cai KQ, Litwin S, Peng H, Karar J, Rauscher FJ, Testa JR. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74(16):4388–97.

    Article  CAS  Google Scholar 

  24. LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, Micol JB, Durham B, Knutson SK, Campbell JE, Blum G, Shi X, Doud EH, Krivtsov AV, Chung YR, Khodos I, de Stanchina E, Ouerfelli O, Adusumilli PS, Thomas PM, Kelleher NL, Luo M, Keilhack H, Abdel-Wahab O, Melnick A, Armstrong SA, Levine RL. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21(11):1344–9.

    Article  CAS  Google Scholar 

  25. Marchesi I, Bagella L. Targeting enhancer of zeste homolog 2 as a promising strategy for cancer treatment. World J Clin Oncol. 2016;7(2):135–48.

    Article  Google Scholar 

  26. Ribrag V, Italiano A, Soria JC, Michot JM, Schmidt A, Postel-Vinay S, Bijou F, Coindre JM, Toulmonde M, Massard C, Blakemore SJ, Mcdonald A, Ribich S, Thomson B, Keilhack H, Roche M, Larus J, Ho PT. Phase 1 study of tazemetostat (EPZ-6438), an inhibitor of EZH2, in patients with non-Hodgkin lymphoma and solid tumors. 13th International Conference of the International Mesothelioma Interest Group. Birmingham: iMig; 2016. p. 6. abstracts book; PL04.03

    Google Scholar 

  27. Mansfield AS, Roden AC, Peikert T, Sheinin YM, Harrington SM, Krco CJ, Dong H, Kwon ED. B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol. 2014;9(7):1036–40.

    Article  CAS  Google Scholar 

  28. Cedrés S, Ponce-Aix S, Zugazagoitia J, Sansano I, Enguita A, Navarro-Mendivil A, Martinez-Marti A, Martinez P, Felip E. Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). PLoS One. 2015;10(3):e0121071.

    Article  Google Scholar 

  29. Calabrò L, Maio M. Immune checkpoint blockade in malignant mesothelioma: a novel therapeutic strategy against a deadly disease? Oncoimmunology. 2014;3:e27482.

    Article  Google Scholar 

  30. Kindler HL, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Ibrahim RA, Taboada M, Puglisi M, Stockman PK, Maio M. Tremelimumab as 2nd- or 3rd-line treatment of unresectable malignant mesothelioma (MM): results from the global, double-blind, placebo-controlled DETERMINE study. Chicago: American Society of Clinical Oncology (ASCO); 2016.

    Google Scholar 

  31. •• Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, van Brummelen E. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017 Mar 10 [Epub ahead of print] This is a small and heterogeneous series of 25 MPM patients issued a phase 1 basket trial in solid tumors. However, it represents the first promising report of immune checkpoint inhibitors in the treatment of MPM.

  32. Tang Z, Qian M, Ho M. The role of mesothelin in tumor progression and targeted therapy. Anti Cancer Agents Med Chem. 2013;13(2):276–80.

    Article  CAS  Google Scholar 

  33. Hassan R, Kindler HL, Jahan T, Bazhenova L, Reck M, Thomas A, Pastan I, Parno J, O’Shannessy DJ, Fatato P, Maltzman JD, Wallin BA. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res. 2014;20(23):5927–36.

    Article  CAS  Google Scholar 

  34. Hassan R, Miller AC, Sharon E, et al. Major cancer regressions in mesothelioma after treatment with an antimesothelin immunotoxin and immune suppression. Sci Transl Med. 2013;5(208):208ra147.

    Article  Google Scholar 

  35. Sterman DH, Alley E, Stevenson JP, Friedberg J, Metzger S, Recio A, Moon EK, Haas AR, Vachani A, Katz SI, Sun J, Heitjan D, Hwang WT, Litzky L, Yearley JH, Tan KS, Papasavvas E, Kennedy P, Montaner L, Cengel KA, Simone CB, Culligan M, Langer C, Albelda SM. Pilot and feasibility trial of immune-gene therapy of malignant pleural mesothelioma using intrapleural delivery of adenovirus-interferon-alpha combined with chemotherapy. Clin Cancer Res. 2016;22(15):3791–800.

    Article  CAS  Google Scholar 

  36. Cornelissen R, Hegmans JP, Maat AP, Kaijen-Lambers ME, Bezemer K, Hendriks RW, Hoogsteden HC, Aerts JG. Extended tumor control after dendritic cell vaccination with low-dose cyclophosphamide as adjuvant treatment in patients with malignant pleural mesothelioma. Am J Respir Crit Care Med. 2016;193(9):1023–31.

    Article  CAS  Google Scholar 

  37. Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, Cheney RT, Chirieac LR, D’Amico TA, Dilling T, Dobelbower M, Govindan R, Hennon M, Horn L, Jahan TM, Komaki R, Lackner RP, Lanuti M, Lilenbaum R, Lin J, Loo BW Jr, Martins R, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Sharma N, Swanson SJ, Stevenson J, Tauer K, Yang SC, Gregory K, Hughes M. NCCN guidelines insights: malignant pleural mesothelioma, version 3.2016. J Natl Compr Cancer Netw. 2016;14(7):825–36.

    Article  Google Scholar 

  38. Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer. 2014;83(2):240–5.

    Article  Google Scholar 

  39. •• de Perrot M, Feld R, Leighl NB, Hope A, Waddell TK, Keshavjee S, Cho BC. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2016;151(2):468–73. This trial and the study from Friedberg et al. below report the best outcome in MPM patients using multimodal treatment, even if these patients were quite selected.

    Article  Google Scholar 

  40. •• Friedberg JS, Simone CB II, Culligan MJ, Barsky AR, Doucette A, McNulty S, Hahn SM, Alley E, Sterman DH, Glatstein E, Cengel KA. Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a median survival of nearly three years. Ann Thorac Surg. 2017; 103(3): 912-9.

    Article  Google Scholar 

  41. Scherpereel A. Malignant pleural mesothelioma: new treatments, new hopes? Eur Respir J. 2017; 49 (3) [Epub ahead of print]

    Article  Google Scholar 

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Acknowledgements

The author would like to thank Professor Loïc Lang-Lazdunski (London, UK) for his review of the manuscript.

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Authors and Affiliations

  1. Pulmonary and Thoracic Oncology, CHU de Lille, Univ Lille, F59000, Lille, France

    Arnaud Scherpereel

  2. French National Network of Clinical Expert Centres for Malignant Pleural Mesothelioma Management (MESOCLIN), Lille, France

    Arnaud Scherpereel

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Correspondence to Arnaud Scherpereel.

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Conflict of Interest

Arnaud Scherpereel reports grants from Roche SA and was the principal investigator of clinical trials supported by Roche. He also reports grants from Boehringer-Ingelheim, Epizyme, Verastem, Bayer, MSD, BMS, and MedImmune.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Pleural Diseases and Mesothelioma

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Scherpereel, A. Chemotherapy for Malignant Pleural Mesothelioma: Past, Present and Future. Curr Pulmonol Rep 6, 155–159 (2017). https://doi.org/10.1007/s13665-017-0179-7

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