title: Limited cardiotoxicity after extensive thoracic surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin.
abstract: BACKGROUND
  Recently, pleural mesothelioma has been treated by cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin. The well-established cardiotoxicity of doxorubicin and distressing data from an animal study raised concern about its impact on cardiac function. In the present study, early cardiotoxicity of this treatment modality was prospectively analyzed.
  
  
  METHODS
  In 13 pleural mesothelioma patients, cardiotoxicity was monitored by clinical examination, electrocardiography, Troponin levels, cardiac ultrasonography, and estimation of left ventricular ejection fraction (LVEF) by radionuclide ventriculography before and during the first 6 months after cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin (25-54 mg/m(2)) and cisplatin (65-120 mg/m(2)).
  
  
  RESULTS
  No clinical cardiac failure or treatment-related death was observed. In two patients transient atrial fibrillation was noted; one associated with pulmonary emboli. Early posttreatment Troponin release was not of predictive value. Ultrasonography did not reveal significant alterations. LVEF decreased significantly (mean 0.07 or 11%, P = .001) during the first 3 months and remained stable thereafter. In univariate analysis, the degree of LVEF reduction was statistically related to maximal intrathoracic doxorubicin concentration (P = .031) and total cisplatin dose (P = .029). Direct exposure of the heart to the drugs as a result of partial pericardectomy was not associated with greater LVEF decrease. On the contrary, partial pericardectomy seemed to be associated with a smaller LVEF decline than when the pericardium remained intact (P = .045). In this small series, no statistically significant correlation between other treatment or pharmacokinetic parameters and LVEF decline was found. Notably, higher doxorubicin plasma concentrations and exposure were not associated with increased LVEF reduction.
  
  
  CONCLUSIONS
  Early cardiotoxicity is limited after this treatment modality using substantial doses of doxorubicin and cisplatin. Hence, this study suggests that intrathoracic chemotherapy with doxorubicin and/or cisplatin may be used for primary and secondary pleural malignancies, even immediately after extensive thoracic surgery, without concern of severe early cardiotoxicity.
authors.affiliation: Department of Surgical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. debree@edu.uoc.gr
authors.forename: Eelco
authors.initials: E
authors.lastname: de Bree
authors.forename: Serge
authors.initials: S
authors.lastname: van Ruth
authors.forename: Carl E
authors.initials: CE
authors.lastname: Schotborgh
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
authors.forename: Frans A N
authors.initials: FA
authors.lastname: Zoetmulder
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D001281:Atrial Fibrillation / Q000097:blood / Q000139:chemically induced; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced*; D010478:Chemotherapy, Cancer, Regional Perfusion; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004452:Echocardiography / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008654:Mesothelioma / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010492:Pericardiectomy; D010997:Pleural Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D013318:Stroke Volume / Q000187:drug effects; D013908:Thoracotomy; D020107:Troponin T / Q000097:blood; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000139:chemically induced
chemical_list: D020107:Troponin T; D004317:Doxorubicin; D002945:Cisplatin