title: Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction - a prospective cohort pilot study within a randomized clinical trial.
abstract: BACKGROUND
  Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy.
  
  
  METHODS
  Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups.
  
  
  RESULTS
  40 patients participated (chemoradiotherapy, n=17; chemotherapy, n=23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p=0.02, p=0.01, and p=0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p=0.09 and p=0.09). NT-proBNP increased following chemoradiotherapy (p=0.05) but not after chemotherapy (p>0.99), and there was a trend towards an interaction effect (p=0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p=0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p=0.10).
  
  
  CONCLUSIONS
  Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function.
  
  
  BACKGROUND
  Clinical Trials.gov NCT01362127 .
authors.affiliation: Department of Anaesthesiology and Intensive Care, and Division of Anaesthesiology, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. mikael.lund@karolinska.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Lund
authors.affiliation: Department of Clinical Oncology and Division of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden. Gabriella.AlexanderssonvonDobeln@karolinska.se.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Alexandersson von Döbeln
authors.affiliation: Department of Surgery and Division of Surgery, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. Magnus.Nilsson@ki.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: Department of Medicine, Section of Cardiology, and Division of Cardiology, Karolinska Institutet, Karolinska University hospital Huddinge, 141 86, Stockholm, Sweden. Reidar.Winter@karolinska.se.|School of Technology and Health, Royal Institute of Technology, Stockholm, Sweden. Reidar.Winter@karolinska.se.
authors.forename: Reidar
authors.initials: R
authors.lastname: Winter
authors.affiliation: Department of Surgery and Division of Surgery, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. Lars.Lundell@karolinska.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Lundell
authors.affiliation: Department of Surgery and Division of Surgery, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. jon.tsai@ki.se.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Tsai
authors.affiliation: Department of Anaesthesiology and Intensive Care, and Division of Anaesthesiology, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. Sigridur.Kalman@Karolinska.se.
authors.forename: Sigridur
authors.initials: S
authors.lastname: Kalman
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059248:Chemoradiotherapy / Q000009:adverse effects*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D004452:Echocardiography; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy*; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D020360:Neoadjuvant Therapy / Q000009:adverse effects*; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000378:metabolism; D010865:Pilot Projects; D011379:Prognosis; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced*
chemical_list: D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D002945:Cisplatin; D005472:Fluorouracil