title: The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: An international multicenter study of 1532 patients treated with chemoimmunotherapy.
abstract: Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown.
  
  
  
  We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS.
  
  
  
  Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2-21.2%) compared with 2.6% (95% CI 1.7-3.5) among those with ≤2 sites (P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values.
  
  
  
  Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication.
authors.affiliation: Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Sdr. Skovvej 15, 9100 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark. Electronic address: tarec.galaly@gmail.com.
authors.forename: Tarec Christoffer
authors.initials: TC
authors.lastname: El-Galaly
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, 150-686 W. Broadway, Vancouver, BC, Canada.
authors.forename: Diego
authors.initials: D
authors.lastname: Villa
authors.affiliation: Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark.
authors.forename: Thomas Yssing
authors.initials: TY
authors.lastname: Michaelsen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9 DK-2100 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Hutchings
authors.affiliation: Department of Clinical Oncology, Guy's and St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Nabegh George
authors.initials: NG
authors.lastname: Mikhaeel
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, 150-686 W. Broadway, Vancouver, BC, Canada.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, 150-686 W. Broadway, Vancouver, BC, Canada.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sehn
authors.affiliation: PET Imaging Centre, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Barrington
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9 DK-2100 Copenhagen, Denmark.
authors.forename: Jakob W
authors.initials: JW
authors.lastname: Hansen
authors.affiliation: Department of Clinical Oncology, Guy's and St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Haematology, Peter MacCallum Cancer Centre and University of Melbourne, 305 Grattan Street, Melbourne VIC 3000, Australia.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Rady
authors.affiliation: Department of Hematology, Odense University Hospital, Søndre Boulevard 29, DK-5000 Odense, Denmark.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Mylam
authors.affiliation: Department of Hematology, Odense University Hospital, Søndre Boulevard 29, DK-5000 Odense, Denmark.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Larsen
authors.affiliation: Department of Hematology, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Staffan
authors.initials: S
authors.lastname: Holmberg
authors.affiliation: Department of Hematology, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark.
authors.forename: Maja B
authors.initials: MB
authors.lastname: Juul
authors.affiliation: Department of Hematology, Roskilde Hospital, Zealand University Hospital, Sygehusvej 10, DK-4000 Roskilde, Denmark.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cordua
authors.affiliation: Department of Hematology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus, Denmark.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clausen
authors.affiliation: Department of Hematology, Holstebro Hospital, Lægårdvej, DK-7500 Holstebro, Denmark.
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Jensen
authors.affiliation: Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Sdr. Skovvej 15, 9100 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
authors.affiliation: Department of Haematology, Peter MacCallum Cancer Centre and University of Melbourne, 305 Grattan Street, Melbourne VIC 3000, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, 150-686 W. Broadway, Vancouver, BC, Canada.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9 DK-2100 Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: de Nully Brown
authors.affiliation: Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Sdr. Skovvej 15, 9100 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
authors.affiliation: Department of Haematology, Peter MacCallum Cancer Centre and University of Melbourne, 305 Grattan Street, Melbourne VIC 3000, Australia; Department of Hematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine, Hospital Ave, Nedlands WA 6009, Australia; University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.
authors.forename: Chan Y
authors.initials: CY
authors.lastname: Cheah
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000000981:diagnostic imaging* / Q000517:prevention & control / Q000556:secondary; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000000981:diagnostic imaging* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging* / Q000517:prevention & control; D000072078:Positron Emission Tomography Computed Tomography; D011241:Prednisone / Q000008:administration & dosage; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
keywords: CNS prophylaxis; CNS relapse; CNS-IPI; Diffuse large B-cell lymphoma; PET/CT; Prognosis; Secondary CNS involvement