title: Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.
abstract: BACKGROUND
  No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients.
  
  
  METHODS
  In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594.
  
  
  RESULTS
  Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity.
  
  
  CONCLUSIONS
  In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population.
  
  
  BACKGROUND
  Schering-Plough/Merck and French Government.
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.affiliation: Aix-Marseille Université, APHM, Service de Neuro-Oncologie, CHU Timone, Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chinot
authors.affiliation: Service de Neurologie, Centre Hospitalier de Nancy, Nancy, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Taillandier
authors.affiliation: Service d'Hématologie, Centre Léon Bérard, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Ghesquieres
authors.affiliation: Service d'Hématologie, Institut Curie-René Huguenin, Saint Cloud, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Soussain
authors.affiliation: Service d'Oncologie Hématologique et de Thérapie Cellulaire, CHU de Poitiers, INSERM, CIC 1402, Poitiers, Centre d'Investigation Clinique, Université de Poitiers, Poitiers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Delwail
authors.affiliation: Service d'Hématologie Clinique, CHU-Hôpital Pontchaillou de Rennes, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: Hématologie Clinique, Hôpital A Michallon, Grenoble, Université Joseph Fourier-Grenoble 1, Institut Albert Bonniot, Faculté de Médecine, La Tronche, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Gressin
authors.affiliation: APHP, UPMC, Service d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
authors.affiliation: Service d'Hématologie, InstitutBergonie, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Soubeyran
authors.affiliation: Service d'Oncologie-Radiothérapie, CHU Bordeaux, Hôpital St André, Bordeaux, France.
authors.forename: Aymeri
authors.initials: A
authors.lastname: Huchet
authors.affiliation: CHU Rangueil, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benouaich-Amiel
authors.affiliation: Service d'Oncologie Médicale, Institut de Cancérologie de l'Ouest, Site René Gauducheau, Saint Herblain, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebouvier-Sadot
authors.affiliation: Service d'Hématologie et Thérapie Cellulaire, CHU de Tours, Tours, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.affiliation: APHP, Groupe Hospitalier Pitié-Salpêtrière, Service d'Ophtalmologie, Sorbonne Universités, UPMC, DHU Vision et Handicap, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Touitou
authors.affiliation: Aix-Marseille Université, APHM, Service de Neuro-Oncologie, CHU Timone, Marseille, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Barrié
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Monica Sierra
authors.initials: MS
authors.lastname: del Rio
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gonzalez-Aguilar
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Houillier
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Delgadillo
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.affiliation: APHP, Unité de Recherche Clinique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Marie Laure
authors.initials: ML
authors.lastname: Tanguy
authors.affiliation: APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Electronic address: khe.hoang-xuan@psl.aphp.fr.
authors.forename: Khê
authors.initials: K
authors.lastname: Hoang-Xuan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D011344:Procarbazine / Q000008:administration & dosage / Q000627:therapeutic use*; D011446:Prospective Studies; D011788:Quality of Life; D000077204:Temozolomide; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003561:Cytarabine; D011344:Procarbazine; D014750:Vincristine; D003606:Dacarbazine; D000077204:Temozolomide; D008727:Methotrexate