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Commentary: Winning the battle for local control without losing war for survival against malignant pleural mesothelioma

  • Alejandro Bribriesco
    Correspondence
    Address for reprints: Alejandro Bribriesco, MD, Section of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, 9500 Euclid Ave/Mailstop J4-1, Cleveland, OH 44195.
    Affiliations
    Section of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio
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      Curative treatment of mesothelioma includes aggressive local disease control. To optimize survival, pursuit of microscopic tumor destruction must be balanced by physiologic cost to the patient.
      See Article page 1510.
      Malignant pleural mesothelioma (MPM) remains vexing despite decades of therapeutic refinement. Curative local control involves cytoreductive surgery (CS) by extrapleural pneumonectomy (EPP) or lung-sparing techniques like pleurectomy/decortication (PD). As part of multimodality therapy, the goal of CS is macroscopic complete resection.
      • Sugarbaker D.J.
      Macroscopic complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma.
      ,
      • Rusch V.
      • Baldini E.H.
      • Bueno R.
      • De Perrot M.
      • Flores R.
      • Hasegawa S.
      • et al.
      The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the international mesothelioma interest group congress, September 11-14, 2012, Boston, Mass.
      Intraoperative adjuncts to increase tumor destruction include intracavitary therapy with hyperthermic intraoperative chemotherapy (HIOC) and photodynamic therapy (PDT).
      • Bertoglio P.
      • Aprile V.
      • Ambrogi M.C.
      • Mussi A.
      • Lucchi M.
      The role of intracavitary therapies in the treatment of malignant pleural mesothelioma.
      While newer intrapleural therapies such as cytokines and oncolytic viral constructs are being explored, we are reminded to reassess “traditional” MPM therapies.
      • Bertoglio P.
      • Aprile V.
      • Ambrogi M.C.
      • Mussi A.
      • Lucchi M.
      The role of intracavitary therapies in the treatment of malignant pleural mesothelioma.
      ,
      • Pease D.F.
      • Kratzke R.A.
      Oncolytic viral therapy for mesothelioma.
      In this issue of the Journal, Hod and colleagues
      • Hod T.
      • Freedberg K.
      • Motwani S.S.
      • Chen M.
      • Frendl G.
      • Leaf D.E.
      • et al.
      Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma.
      from Brigham and Women's Hospital present a retrospective study of 501 patients with MPM who underwent CS (48% EPP), with 82% receiving cisplatin-based HIOC using a phase I/II-established protocol including renal protection.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • Jaklitsch M.R.
      • Chirieac L.R.
      • Johnson B.E.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • Jaklitsch M.T.
      • Jänne P.A.
      • Chirieac L.R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Burt B.M.
      • Richards W.G.
      • Lee H.S.
      • Bartel S.
      • Dasilva M.C.
      • Gill R.R.
      • et al.
      A phase I trial of surgical resection and intraoperative hyperthermic cisplatin and gemcitabine for pleural mesothelioma.
      The aim was to assess acute kidney injury (AKI) with a simple but important hypothesis: AKI is more common in patients receiving CS + HIOC. The overall incidence of AKI was 48.3% and significantly greater with HIOC (53.5% vs 24.2%). AKI was more common in EPP versus PD, and stage III AKI was associated with increased length of stay and risk of death. Notably, the observed survival benefit of CS + HIOC was limited to patients who did not develop AKI. This study was not designed to assess cancer-specific outcomes and so no data are presented on disease-free survival (DFS) or overall survival (OS). However, an impactful finding is that HIOC-associated AKI compromised the therapeutic benefit of aggressive local control.
      Patient selection is critical to improving MPM outcomes. In previous work, the Brigham and Women's Hospital group created a tool based on 3 variables (epithelioid histology, anemia, tumor volume) predicting low-risk patients receiving EPP.
      • Gill R.R.
      • Richards W.G.
      • Yeap B.Y.
      • Matsuoka S.
      • Wolf A.S.
      • Gerbaudo V.H.
      • et al.
      Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume.
      Applied ad hoc to patients with CS undergoing HIOC, 103 low-risk patients were identified with excellent median OS for the entire cohort (33.1 months).
      • Sugarbaker D.J.
      • Gill R.R.
      • Yeap B.Y.
      • Wolf A.S.
      • DaSilva M.C.
      • Baldini E.H.
      • et al.
      Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection.
      With the current study, risk of AKI could be factored to create a tailored approach with PD and non-nephrotoxic intrapleural agent. This is supported by studies of lung-preserving surgery with PDT
      • Friedberg J.S.
      • Simone II, C.B.
      • Culligan M.J.
      • Barsky A.R.
      • Doucette A.
      • McNulty S.
      • et al.
      Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a median survival of nearly three years.
      and povidone–iodine,
      • Lang-Lazdunski L.
      • Bille A.
      • Papa S.
      • Marshall S.
      • Lal R.
      • Galeone C.
      • et al.
      Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience.
      which reported a median OS of 36 and 32 months, respectively.
      Evidence that decreased local recurrence is not equivalent to improved survival disrupts justification of collateral damage in pursuit of local control. Friedberg and colleagues'
      • Friedberg J.S.
      • Simone II, C.B.
      • Culligan M.J.
      • Barsky A.R.
      • Doucette A.
      • McNulty S.
      • et al.
      Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a median survival of nearly three years.
      PD + PDT study showed significant discordance between DFS (median 14 months) and OS (median 36 months for cohort; 87 months for low-risk subgroup). Similarly, series of lung-sparing CS plus povidone–iodine
      • Lang-Lazdunski L.
      • Bille A.
      • Papa S.
      • Marshall S.
      • Lal R.
      • Galeone C.
      • et al.
      Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience.
      and HIOC
      • Ambrogi M.C.
      • Bertoglio P.
      • Aprile V.
      • Chella A.
      • Korasidis S.
      • Fontanini G.
      • et al.
      Diaphragm and lung-preserving surgery with hyperthermic chemotherapy for malignant pleural mesothelioma: a 10-year experience.
      reported median OS between 22 and 32 months despite recurrence up to 90%. Recently, Batirel and colleagues
      • Batirel H.F.
      • Metintas M.
      • Caglar H.B.
      • Ak G.
      • Yumuk P.F.
      • Ahiskali R.
      • et al.
      Macroscopic complete resection is not associated with improved survival in patients with malignant pleural mesothelioma.
      showed no survival advantage to macroscopic complete resection with CS in both unmatched and propensity-matched patients. In contrast, Tilleman and colleagues'
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • Johnson B.E.
      • Jaklitsch M.T.
      • Mueller J.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      study of EPP + HIOC showed ipsilateral hemithorax recurrence dropped to 31.5% with DFS of 15.3 months, but median OS achieved was 13.1 months.
      Local disease control has been equated to improved survival with MPM.
      • Sugarbaker D.J.
      • Flores R.M.
      • Jaklitsch M.T.
      • Richards W.G.
      • Strauss G.M.
      • Corson J.M.
      • et al.
      Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.
      This is now being challenged, as physiologic cost associated with winning the battle for local control may not win the war for survival. Understanding the interplay of patient factors and therapeutic weapons is essential in the fight against MPM.

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