High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

Department of Hematology and Oncology, Charité Berlin, Berlin, Germany.
The Lancet Oncology (Impact Factor: 24.69). 10/2010; 11(11):1036-47. DOI: 10.1016/S1470-2045(10)70229-1
Source: PubMed

ABSTRACT High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival.
Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with, number NCT00153530.
551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%).
No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

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    • "Studies on replacement of WBRT with conventional chemotherapy are still limited [8,9]. Findings of a phase 3 randomized clinical trial (G-PCNSL-SG-1) showed no significant difference in overall survival (OS) when WBRT was skipped after first-line chemotherapy, however, a disadvantage in progression-free survival (PFS) was proven regardless of chemotherapy response [10]. Therefore, it was thought that the benefit of WBRT in terms of PFS outweighed the increased risk of NT. "
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    ABSTRACT: Purpose The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL). Materials and Methods We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively. Results With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025). Conclusion Low-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.
    Cancer Research and Treatment 07/2014; 46(3):261-269. DOI:10.4143/crt.2014.46.3.261 · 3.32 Impact Factor
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    • "Following introduction of HD-MTX-based chemotherapy, WBRT (36-45Gy) has continued to be employed to consolidate responses and provide more durable disease control. Delayed neurotoxicity [58, 59•], however, is a major limitation that is clinically evident in approximately one-third of patients, particularly with increasing age, and associated with significant morbidity and mortality. The only phase III trial thus far to complete accrual in PCNSL aimed to demonstrate that omission of consolidation WBRT after MTX-based chemotherapy resulted in non-inferior OS rates. "
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    ABSTRACT: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system is an aggressive malignancy that exhibits unique biological features and characteristic clinical behaviour, with overall long-term survival rates of around 20-40 %. Clinical outcome has improved following the advent of chemoradiation protocols incorporating high-dose methotrexate in the mid-1980s, but disease relapse and adverse neurocognitive sequelae remain major clinical challenges. To address this, investigators have focused on improving drug therapy with novel cytotoxic combinations, monoclonal antibody therapy, and intensive chemotherapy consolidation approaches, in an attempt to improve disease control whilst reducing the requirement for whole-brain radiotherapy. Outcomes for patients that are older, immunocompromised, or have relapsed/refractory disease remain unsatisfactory and there is a paucity of clinical trial data to guide treatment of these groups. This review highlights recent advances in pathobiology, imaging, and clinical management of PCNSL and looks ahead to research priorities for this rare and challenging lymphoid malignancy.
    Current Hematologic Malignancy Reports 06/2014; 9(3). DOI:10.1007/s11899-014-0217-2 · 2.20 Impact Factor
    • "The German PCNSL study group conducted a phase III trial where patients were randomized to receive HD-MTX–based chemotherapy with or without WBRT [26••]. A total of 551 patients were enrolled of whom 318 were treated per protocol. "
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    ABSTRACT: Opinion statement Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn’t been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity.
    Current Treatment Options in Oncology 12/2013; 14(4). DOI:10.1007/s11864-013-0252-6 · 3.24 Impact Factor
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