title: Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer.
abstract: BACKGROUND
  Although prognostic parameters are important to guide adjuvant treatment, very few have been identified in patients with completely resected adrenocortical carcinoma (ACC).
  
  
  OBJECTIVE
  To assess the prognostic role of clinical symptoms of hypercortisolism in a large series of patients with completely resected ACC.
  
  
  METHODS
  A total of 524 patients followed at referral centers for ACC in Europe and the United States entered the study. Inclusion criteria were ≥18 yr of age, a histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of other malignancies and adjuvant systemic therapies other than mitotane.
  
  
  METHODS
  All ACC patients were completely resected, and adjuvant mitotane therapy was prescribed at the discretion of the investigators.
  
  
  METHODS
  The primary end point was overall survival (OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of adjuvant mitotane therapy according to cortisol secretion.
  
  
  CONCLUSIONS
  Overt hypercortisolism was observed in 197 patients (37.6%). Patients with cortisol excess were younger (p=0.002); no difference according to sex and tumor stage was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age, tumor stage, and mitotane treatment, the prognostic significance of cortisol excess was highly significant for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04-2.62; p=0.02) and OS (HR: 1.55; 95% CI, 1.15-2.09; p=0.004). Mitotane administration was associated with a reduction of disease progression (adjusted HR: 0.65; 95% CI, 0.49-0.86; p=0.003) that did not differ according to the patient's secretory status. A major limitation is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome.
  
  
  CONCLUSIONS
  Clinically relevant hypercortisolism is a new prognostic factor in patients with completely resected ACC. The efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism.
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy. Electronic address: alfredo.berruti@gmail.com.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.affiliation: Department of Internal Medicine IV, University Clinic, Munich, Germany; Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Internal Medicine, Maxima Medical Centre, Eindhoven, The Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: Haak
authors.affiliation: Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Else
authors.affiliation: Endocrine Oncology and Nuclear Medicine, Gustave Roussy Institute, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Department of Oncology, University of Turin, Medical Oncology Unit, San Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sperone
authors.affiliation: Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kroiss
authors.affiliation: Internal Medicine, Maxima Medical Centre, Eindhoven, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kerkhofs
authors.affiliation: Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Williams
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Internal Medicine I, S. Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Ardito
authors.affiliation: Endocrine Oncology and Nuclear Medicine, Gustave Roussy Institute, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.affiliation: Department of Oncology, University of Turin, Pathology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.affiliation: Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Deutschbein
authors.affiliation: Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Richards
authors.initials: R
authors.lastname: Feelders
authors.affiliation: Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ronchi
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grisanti
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Oncology, University of Turin, Urology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Porpiglia
authors.affiliation: Department of Oncology, University of Turin, Pathology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.affiliation: Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Internal Medicine I, S. Luigi Gonzaga Hospital, Orbassano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000601:surgery*; D018268:Adrenocortical Carcinoma / Q000150:complications / Q000601:surgery*; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D003480:Cushing Syndrome / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000627:therapeutic use*; D011379:Prognosis; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane
keywords: Adjuvant therapy; Adrenocortical cancer; Cushing syndrome; Mitotane