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.
Objectives
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.
Search 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.
Selection criteria
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.
Data collection and analysis
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.
Main 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).
Authors’ 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.
Plain language summary
The role of brain radiotherapy (X-rays) in the treatment of lymphoma in the brain
Background: Primary central nervous system lymphoma (PCNSL) is a type of cancer that occurs in the brain or spinal cord. It is a rare and aggressive type of lymphoma. People who develop PCNSL survive for only four months on average, if they do not receive treatment. For a long time the only treatment showing any benefit was whole brain radiotherapy (WBR), in which X-rays are used to destroy cancerous cells in the brain. However, several studies suggest that this treatment method also produces signs of damage to healthy brain tissue. Since the introduction of methotrexate, a powerful chemotherapy drug showing great beneficial effects, experts have debated the role of radiotherapy in the treatment of people with PCNSL. Radiotherapy could be combined with chemotherapy, or not used at all, especially considering its potentially harmful effects.
Review question: The aim of this review was to find any scientific studies of high quality that focus on the effectiveness and harmful effects of radiotherapy in the treatment of PCNSL. A broad search of all relevant databases produced 556 references regarding this topic. Only one study fulfilled the strict inclusion criteria and was thus analysed in detail.
Study characteristics: We searched all databases for relevant studies published between January 1950 and February 2014. We included only one study that enrolled 551 participants and treated one half with methotrexate followed by WBR, and the other half with methotrexate alone. If participants in the latter group did not respond sufficiently to methotrexate alone, another drug, cytarabine, was given. Participants of a minimum of 18 years of age were enrolled at 75 centres in Germany between May 2000 and May 2009.
Key results: When we analysed the data regarding the effect of chemotherapy plus WBR or chemotherapy alone on overall survival, the results were imprecise and either treatment could have been superior to the other. Another outcome we considered in addition to overall survival was progression-free survival (PFS), a state in which the disease does not get any worse. The addition of radiotherapy to chemotherapy had a positive effect on PFS, slightly extending the period in which the disease did not progress in comparison to that acheived with chemotherapy alone. The authors did not analyse treatment-related mortality.
We also looked at whether treatment resulted in any damage to healthy brain tissue during treatment. We found no evidence that treatment-related symptoms of brain function impairment were more common in the group of participants receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone.
Quality of evidence: We consider the quality of the evidence body as moderate to low, as we included only one trial with a small number of participants. As the included study did not analyse adverse events in all participants, we consider the quality of the evidence for the outcome of neurotoxicity as very low.
Conclusion: In summary, the currently available evidence (one randomised controlled trial) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The addition of WBR to chemotherapy may increase progression-free survival, but could possibly also increase levels of toxic effects on the brain. Further prospective randomised trials are needed before definitive conclusions can be drawn about the role of adding radiotherapy to chemotherapy in the treatment of PCNSL.
