Closing faucets: the role of anti-angiogenic therapies in malignant pleural diseases
- 567 Downloads
Malignant pleural effusion (MPE) represents 15–35 % of pleural effusions and markedly worsens the prognosis and quality of life of patients with cancer. Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE. Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patient life. Since angiogenesis plays a key role in MPE development, the potential role of bevacizumab and other anti-angiogenic therapies have been explored in this review. No relevant phase III trials have specifically analysed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE. However, small retrospective series reported 71.4–93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination. Being approved for the first-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE. In addition, further studies in this are recommended. In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary endpoints in two phase II trials. However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM. To date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM. However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation.
KeywordsAnti-angiogenesis Bevacizumab Malignant pleural effusion Malignant mesothelioma Non-small cell lung cancer
The Spanish Society of Medical Oncology (SEOM) supported the collaboration of D.M. as Honorary Observer in the Royal Marsden Hospital. S.P. acknowledges NHS funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre.
Compliance with ethical standards
Conflict of interest
S.P. is consultant to AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Pfizer, and Roche. D.M. has participated as speaker and advisor for Roche, Boehringer Ingelheim, Astra-Zeneca, Lilly, Novartis, and Pierre-Fabre events.
Informed consent and participants
The present review did not involve human participants or animals. So, the asking of informed consent was not necessary.
- 5.Fiorelli A, Vicidomini G, Di Domenico M, Napolitano F, Messina G, Morgillo F, et al. Vascular endothelial growth factor in pleural fluid for differential diagnosis of benign and malignant origin and its clinical applications. Interact Cardiovasc Thorac Surg. 2011;12:420–4.CrossRefPubMedGoogle Scholar
- 9.Gkiozos I, Tsagouli S, Charpidou A, Grapsa D, Kainis E, Gratziou C, et al. Levels of vascular endothelial growth factor in serum and pleural fluid are independent predictors of survival in advanced non-small cell lung cancer: results of a prospective study. Anticancer Res. 2015;35:1129–37.PubMedGoogle Scholar
- 11.Qian Q, Zhan P, Sun WK, Zhang Y, Song Y, Yu LK. Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: correlations with patient survival and pleural effusion control. Neoplasma. 2012;59:433–9.CrossRefPubMedGoogle Scholar
- 26.Karrison T, Kindler HL, Gandara DR, Lu C, Guterz TL, Nichols K, et al. Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients (pts) with malignant mesothelioma. J Clin Oncol. 2007;25:S391.Google Scholar
- 29.Matsumori Y, Yano S, Goto H, Nakataki E, Wedge SR, Ryan AJ, et al. ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model. Oncol Res. 2006;16:15–26.PubMedGoogle Scholar
- 30.Shibuya K, Komaki R, Shintani T, Itasaka S, Ryan A, Jürgensmeier JM, et al. Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;69:1534–43.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Fujii M, Iwakami SI, Ihara H, Hara M, Iwakami N, Ishiwata T, et al. Efficacy and safety of chemotherapy containing bevacizumab in patients with non-small cell lung cancer with malignant pleural effusion. Respirology. 2013;18:87.Google Scholar
- 42.Santoro A, O’Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008;3:756–63.CrossRefPubMedGoogle Scholar
- 44.Li Q, Yano S, Ogino H, Wang W, Uehara H, Nishioka Y, et al. The therapeutic efficacy of anti vascular endothelial growth factor antibody, bevacizumab, and pemetrexed against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice. Clin Cancer Res. 2007;13:5918–25.CrossRefPubMedGoogle Scholar
- 48.Zalcman G, Mazieres J, Scherpereel A, Margery J, Moro-Sibilot D, Parienti JJ, et al. IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase II–III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma. J Clin Oncol. 2012;30:STPS7112.Google Scholar
- 49.Zalcman G, Mazières J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, et al. Bevacizumab 15 mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial. J Clin Oncol. 2015;33:S7500.Google Scholar
- 51.Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31:3004–11.CrossRefPubMedGoogle Scholar
- 52.Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31:4349–57.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Sartori S, Tassinari D, Ceccotti P, Tombesi P, Nielsen I, Trevisani L, et al. Prospective randomized trial of intrapleural bleomycin versus interferon alfa-2b via ultrasound-guided small-bore chest tube in the palliative treatment of malignant pleural effusions. J Clin Oncol. 2004;22:1228–33.CrossRefPubMedGoogle Scholar
- 56.Kindler HL, Vogelzang NJ, Chien K, Stadler WM, Karczmar G, Heimann R, et al. SU5416 in malignant mesothelioma: a University of Chicago phase II consortium study. Proc Am Soc Clin Oncol. 2001;20:S1359.Google Scholar
- 59.Baas P, Buikhuisen W, Dalesio O, Vincent A, Pavlakis N, Van Klaveren R, et al. A multicenter, randomized phase III maintenance study of thalidomide (arm A) versus observation (arm B) in patients with malignant pleural mesothelioma (MPM) after induction chemotherapy. J Clin Oncol. 2011;29:S7006.Google Scholar