title: Survival outcomes and incidence of brain recurrence in high-grade neuroendocrine carcinomas of the lung: Implications for clinical practice.
abstract: BACKGROUND
  Among patients with advanced high-grade neuroendocrine carcinoma (HGNEC) of the lung, the optimal therapeutic management is much less established for large cell neuroendocrine carcinomas (LCNECs) than for small cell lung cancers (SCLCs). We evaluated the survival outcomes and incidence of brain recurrence of advanced LCNECs, and compared them with those of a population of SCLCs matched by stage.
  
  
  METHODS
  Forty-eight unresected stage III HGNECs (16 LCNECs and 32 SCLCs) and 113 stage IV HGNECs (37 LCNECs and 76 SCLCs) were eligible for the analysis. The efficacy of platinum-etoposide chemotherapy with or without thoracic radiotherapy (TRT) and/or prophylactic cranial irradiation (PCI) was investigated.
  
  
  RESULTS
  Overall response was significantly lower for LCNECs compared with SCLCs for both stage III (43.8% vs 90.6% respectively, P=0.004) and stage IV (43.3% vs 64.5%, respectively, P=0.04). Similarly, an inferior outcome was observed in terms of progression-free survival (PFS), and overall survival (OS) for LCNECs compared with SCLCs, which, however, reached significance only for stage III disease (median: 5.6 vs 8.9 months, P=0.06 and 10.4 vs 17.6 months, P=0.03 for PFS and OS, respectively). In the lack of PCI, LCNECs showed a high cumulative incidence of brain metastases, as 58% and 48% of still living stage III and IV patients, respectively, developed brain metastases at 18 months.
  
  
  CONCLUSIONS
  Patients with advanced LCNECs are at high risk for brain recurrence. Unresected stage III LCNECs treated with platinum-etoposide with or without TRT bear a dismal prognosis, when compared indirectly with SCLC counterparts. Randomized trials should evaluate whether PCI could improve survival of advanced LCNECs.
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Metro
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy. Electronic address: biagio.ricciuti@gmail.com.
authors.forename: Biagio
authors.initials: B
authors.lastname: Ricciuti
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Chiari
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, MI, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Baretti
authors.affiliation: Radiotherapy Unit, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Falcinelli
authors.affiliation: Biostatistics & Data Management Core, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Department of Experimental Medicine, Pathological Anatomy and Histology Unit, University of Perugia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.affiliation: Deparment of Medical Oncology, University of Athens School of Medicine, Athens, Greece.
authors.forename: Giannis
authors.initials: G
authors.lastname: Mountzios
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.affiliation: Department of Experimental Medicine, Pathological Anatomy and Histology Unit, University of Perugia, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Bellezza
authors.affiliation: Department of Diagnostic Imaging, University of Perugia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rebonato
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ferolla
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, MI, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Toschi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000453:epidemiology / Q000401:mortality* / Q000556:secondary* / Q000628:therapy; D018278:Carcinoma, Neuroendocrine / Q000401:mortality* / Q000473:pathology* / Q000628:therapy; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D016896:Treatment Outcome
keywords: Chemotherapy; High-grade neuroendocrine carcinoma of the lung; Large cell neuroendocrine carcinoma of the lung; Platinum-etoposide; Prophylactic cranial irradiation; Small cell lung cancer