title: The role of additional radiotherapy for primary central nervous system lymphoma.
abstract: BACKGROUND
  Prior to the introduction of the chemotherapeutic agent methotrexate, radiotherapy was the sole, first-line option for the treatment of individuals with primary central nervous system lymphoma (PCNSL), Now that methotrexate is available, the role of radiotherapy in the treatment of PCNSL has been called into question. Although various studies suggest promising results with regard to overall and progression-free survival with the use of chemotherapeutic regimens alone as well as in combination with radiotherapy, no evidence-based standard regimen has yet been defined.
  
  
  OBJECTIVE
  The objective of this review was to assess and summarise the evidence available regarding the efficacy and tolerability of radiotherapy in addition to chemotherapy in the treatment of immunocompetent individuals with PCNSL.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 01.2014), MEDLINE from January 1950 to February 2014 and conference proceedings from 2005 to 2013.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing chemotherapy plus radiotherapy with chemotherapy alone in individuals with PCNSL. Outcomes defined in this review were overall survival, progression-free survival, response to treatment, adverse events, treatment related mortality and quality of life. We excluded trials in which the chemotherapy regimen differed between treatment arms, trials in which fewer than 80% of participants had PCNSL or those recruiting immunocompromised individuals with PCNSL.
  
  
  METHODS
  Two review authors independently screened the results of the search strategies for eligibility for this review. Both assessed risk of bias. Where relevant data was unavailable, we contacted the investigator by email.
  
  
  RESULTS
  Of the 556 potentially relevant studies only two met the inclusion criteria. One of those was excluded as the trial was abandoned prematurely and reported only preliminary results. The only analysed trial enrolled 551 participants receiving first-line chemotherapy (methotrexate) followed by whole brain radiotherapy (WBR) or receiving chemotherapy only (methotrexate followed by cytarabine in case of incomplete response). In this non-inferiority trial, the intention-to-treat (ITT) population consisted of 411 participants and the per-protocol (PP) population of 318 participants. We judged the potential for risk of bias in this open-label study as moderate.The estimated effect of chemotherapy plus WBR on survival was similar to that with chemotherapy alone but due to a wide CI we could not rule out the superiority of either therapy. This applied to both the ITT population (HR 1.01, 95% CI 0.79 to 1.30; P = 0.94) and the PP population (HR 1.06, 95% CI 0.80 to 1.40; P = 0.71) (moderate-quality evidence). Due to the low number of participants and a risk of detection bias we found low-quality evidence for an improvement in progression-free survival in participants in the ITT population receiving WBR in addition to chemotherapy (HR 0.79, 95% CI 0.63 to 0.99; P = 0.041). An improvement in PFS was also observed with WBR plus chemotherapy in participants in the PP population, but the CI was slightly wider and the result not significant (HR 0.82,95% CI 0.64 to 1.07; P = 0.14). Treatment-related mortality and health-related quality of life were not evaluated. Treatment-related neurotoxicity was assessed clinically in 79 participants, revealing signs of neurotoxicity in 49% of those receiving chemotherapy plus radiotherapy and in 26% of those receiving chemotherapy only (RR 1.85, 95% CI 0.98 to 3.48; P = 0.054) (very-low-quality evidence).
  
  
  CONCLUSIONS
  In summary, the currently available evidence (one RCT) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The findings suggest that the addition of radiotherapy (WBR) to chemotherapy may increase progression-free survival, but may also increase the incidence of neurotoxicity compared to chemotherapy only (methotrexate monotherapy). As the role of chemoradiotherapy in the treatment of PCNSL remains unclear, further prospective, randomised trials are needed before definitive conclusions can be drawn.
authors.affiliation: Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Zacher
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kasenda
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D016371:Cranial Irradiation / Q000379:methods*; D003561:Cytarabine / Q000627:therapeutic use; D057239:Early Termination of Clinical Trials; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000532:radiotherapy*; D008727:Methotrexate / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D008727:Methotrexate