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Characteristics and Long-term Outcomes of Pulmonary Venoocclusive Disease Induced by Mitomycin C

  • Marie-Caroline Certain
    Affiliations
    Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France
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  • Marie-Camille Chaumais
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Pharmacy, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, Faculty of Pharmacy, Châtenay Malabry, France
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  • Xavier Jaïs
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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  • Laurent Savale
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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  • Andrei Seferian
    Affiliations
    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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  • Florence Parent
    Affiliations
    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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  • Marjolaine Georges
    Affiliations
    Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France

    University of Bourgogne Franche-Comté, School of Medicine, Dijon, France

    INSERM UMR 123-1, LNC Faculty of Medicine and Pharmacy, Dijon, France
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  • Nicolas Favrolt
    Affiliations
    Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France
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  • Arnaud Bourdin
    Affiliations
    Department of Respiratory Diseases, Hôpital Arnaud de Villeneuve, Montpellier University Hospitals, Montpellier, France

    University of Montpellier, School of Medicine, Montpellier, France

    INSERM U1046, Montpellier, France
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  • Clément Boissin
    Affiliations
    Department of Respiratory Diseases, Hôpital Arnaud de Villeneuve, Montpellier University Hospitals, Montpellier, France
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  • Vincent Cottin
    Affiliations
    Department of Respiratory Medicine, National Coordinating Reference Center for Rare Pulmonary Diseases, Hôpital Louis Pradel, Lyon, France

    Claude-Bernard Lyon 1 University, University of Lyon, INRA, UMR754, Lyon, France

    UMR 754, Lyon, France
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  • Julie Traclet
    Affiliations
    Department of Respiratory Medicine, National Coordinating Reference Center for Rare Pulmonary Diseases, Hôpital Louis Pradel, Lyon, France
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  • Sébastien Renard
    Affiliations
    Department of Cardiology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Timone, Aix-Marseille University, Marseille, France
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  • Violaine Noel
    Affiliations
    Internal Medicine Department, Hôpital Robert-Debré, Reims, France
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  • François Picard
    Affiliations
    Department of Cardiology, University Hospital of Bordeaux, Bordeaux, France
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  • Barbara Girerd
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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  • Maria-Rosa Ghigna
    Affiliations
    Department of Pathology, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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  • Frédéric Perros
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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  • Olivier Sitbon
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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  • Philippe Bonniaud
    Affiliations
    Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France

    University of Bourgogne Franche-Comté, School of Medicine, Dijon, France

    INSERM UMR 123-1, LNC Faculty of Medicine and Pharmacy, Dijon, France
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  • Marc Humbert
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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  • David Montani
    Correspondence
    CORRESPONDENCE TO: David Montani, MD, PhD
    Affiliations
    INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

    AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
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Published:September 23, 2020DOI:https://doi.org/10.1016/j.chest.2020.09.238

      Background

      Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported.

      Research Question

      What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?

      Study Design and Methods

      We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum).

      Results

      From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m2), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (–4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively.

      Interpretation

      PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.

      Key Words

      Abbreviations:

      5-FU (5-fluorouracil), 6MWD (6 min-walk test), BMPR2 (gene encoding bone morphogenetic protein receptor type 2), BNP (brain natriuretic peptide), CI (cardiac index), CO (cardiac output), Dlco (diffusing capacity of the lungs for carbon monoxide), EIF2AK4 (gene encoding eukaryotic translation initiation factor 2α kinase 4), ERA (endothelin receptor antagonist), HRCT (high-resolution CT), MMC (mitomycin C), mPAP (mean pulmonary arterial pressure), NT-pro-BNP (N-terminal pro-brain natriuretic peptide), NYHA FC (New York Heart Association functional class), PAH (pulmonary arterial hypertension), PAWP (pulmonary arterial wedge pressure), PDE5i (phosphodiesterase type 5 inhibitor), PH (pulmonary hypertension), PVOD (pulmonary venoocclusive disease), PVR (pulmonary vascular resistance), RAP (right atrial pressure), RHC (right heart catheterization), TLC (total lung capacity), WU (Wood units)
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      References

        • Galiè N.
        • Humbert M.
        • Vachiery J.-L.
        • et al.
        2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
        Eur Respir J. 2015; 46: 903-975
        • Simonneau G.
        • Montani D.
        • Celermajer D.S.
        • et al.
        Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
        Eur Respir J. 2019; 53: 1801913
        • Montani D.
        • Kemp K.
        • Dorfmuller P.
        • Sitbon O.
        • Simonneau G.
        • Humbert M.
        Idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: similarities and differences.
        Semin Respir Crit Care Med. 2009; 30: 411-420
        • Humbert M.
        • Guignabert C.
        • Bonnet S.
        • et al.
        Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.
        Eur Respir J. 2019; 53: 1801887
        • Pietra G.G.
        • Capron F.
        • Stewart S.
        • et al.
        Pathologic assessment of vasculopathies in pulmonary hypertension.
        J Am Coll Cardiol. 2004; 43: S25-S32
        • Montani D.
        • Lau E.M.
        • Dorfmüller P.
        • et al.
        Pulmonary veno-occlusive disease.
        Eur Respir J. 2016; 47: 1518-1534
        • Humbert M.
        • Tre S.M.
        • Capron F.
        • Rain B.
        • Musset D.
        • Simonneau G.
        Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis.
        Am J Respir Crit Care Med. 1998; 157: 1681-1685
        • Eyries M.
        • Montani D.
        • Girerd B.
        • et al.
        EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.
        Nat Genet. 2014; 46: 65-69
        • Montani D.
        • Lau E.M.
        • Descatha A.
        • et al.
        Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease.
        Eur Respir J. 2015; 46: 1721-1731
        • Ranchoux B.
        • Günther S.
        • Quarck R.
        • et al.
        Chemotherapy-induced pulmonary hypertension: role of alkylating agents.
        Am J Pathol. 2015; 185: 356-371
        • Knight B.K.
        • Rose A.G.
        Pulmonary veno-occlusive disease after chemotherapy.
        Thorax. 1985; 40: 874-875
        • Botros L.
        • Van Nieuw Amerongen G.P.
        • Noordegraaf A.V.
        • Bogaard H.J.
        Recovery from mitomycin-induced pulmonary arterial hypertension.
        Ann Am Thorac Soc. 2014; 11: 468-470
        • Gagnadoux F.
        • Capron F.
        • Lebeau B.
        Pulmonary veno-occlusive disease after neoadjuvant mitomycin chemotherapy and surgery for lung carcinoma.
        Lung Cancer. 2002; 36: 213-215
        • Chaumais M.-C.
        • O’Connell C.
        • Savale L.
        • et al.
        Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension.
        Int J Clin Pharm. 2018; 40: 790-794
        • Savale L.
        • Chaumais M.-C.
        • Dorfmuller P.
        • Humbert M.
        • Montani D.
        Lung transplantation for mitomycin-induced pulmonary veno-occlusive disease.
        Presse Med. 2017; 46: 1223-1225
        • Orwoll E.S.
        • Kiessling P.J.
        • Patterson J.R.
        Interstitial pneumonia from mitomycin.
        Ann Intern Med. 1978; 89: 352-355
        • Perros F.
        • Günther S.
        • Ranchoux B.
        • et al.
        Mitomycin-induced pulmonary veno-occlusive disease: evidence from human disease and animal models.
        Circulation. 2015; 132: 834-847
        • Montani D.
        • Girerd B.
        • Jaïs X.
        • et al.
        Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study.
        Lancet Respir Med. 2017; 5: 125-134
      1. Forman D, Bray F, Brewster DH, et al, eds.; International Agency for Research on Cancer; World Health Organization; International Association of Cancer Registries. Cancer incidence in five continents Vol. X. IARC Scientific Publications No. 164. 2014. https://ci5.iarc.fr/cI5I-x/old/vol10/CI5vol10.pdf. Accessed October 24. 2020.

        • Abramowitz L.
        • Rémy V.
        • Vainchtock A.
        Economic burden of anal cancer management in France.
        Rev Epidemiol Sante Publique. 2010; 58: 331-338
        • Nossent E.J.
        • Antigny F.
        • Montani D.
        • et al.
        Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease.
        J Heart Lung Transplant. 2018; 37: 647-655
        • Duperray A.
        • Tranqui L.
        • Alix J.-L.
        • Cordonnier D.
        Effect of mitomycin C on prostacyclin synthesis by human endothelial cells.
        Biochem Pharmacol. 1988; 37: 4753-4757
        • Hoorn C.M.
        • Wagner J.G.
        • Petry T.W.
        • Roth R.A.
        Toxicity of mitomycin C toward cultured pulmonary artery endothelium.
        Toxicol Appl Pharmacol. 1995; 130: 87-94
        • Glynne-Jones R.
        • Nilsson P.J.
        • Aschele C.
        • et al.
        • European Society for Medical Oncology (ESMO); European Society of Surgical Oncology (ESSO); European Society of Radiotherapy and Oncology (ESTRO)
        Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up.
        Eur J Surg Oncol. 2014; 40: 1165-1176