International Journal of Radiation Oncology*Biology*Physics
Clinical investigation: brainClinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate
Introduction
The optimal treatment for primary central nervous system lymphomas (PCNSL) has not been characterized. Uncertainties reflect the heterogeneous management in retrospective series, limited number of published prospective studies, and paucity of randomized trials (1).
Radiotherapy (RT) has been considered the treatment of choice, providing a complete response in most patients, with a median survival of 12–17 months 2, 3 and a 5-year survival of 14–26% 3, 4. When RT was the exclusive treatment, the suggested doses were at least 40 Gy to the whole brain (WB), followed by a boost to the tumor bed (TB) to reach 50 Gy (5).
Some prospective series 6, 7, 8, 9, 10 and critical reviews 4, 5, 11, 12 have demonstrated that the combination of chemotherapy (CHT) with high-dose (≥1 g/m2) methotrexate (HD-MTX) and RT improves the outcome, achieving a median survival of 33–42 months and a 5-year survival of 22–40% 4, 9, 10, 13. However, neither the optimal CHT regimen (5) nor the optimal RT dose and field extent in the combined-treatment modality have been identified.
Severe late toxicity in the range of 32–36% 10, 14 and a poor quality of life in long-term survivors have been reported in patients receiving brain irradiation after CHT. Pursuant to such neurotoxicity, which is responsible for death in one-third of affected patients, it has been proposed to treat PCNSL patients with CHT alone, reserving RT for refractory or recurrent disease. Preliminary results in a few small series with short follow-up times have suggested that survival is not compromised by RT delay 15, 16, 17, 18.
In practice, because of the rarity of PCNSL, prospective randomized trials to address various therapeutic issues that have not been clearly defined are unlikely to be feasible (1). We therefore conducted a retrospective analysis of published prospective series to identify the optimal dose of HD-MTX and to assess the efficacy of other parenteral and intrathecal drugs. In addition we assessed the impact on survival of different RT doses and of RT at recurrence in patients obtaining a complete response (CR) to upfront HD-MTX-containing CHT.
Section snippets
Methods and materials
The clinical and therapeutic data from 357 patients reported in 19 prospective series (Table 1) 6, 8, 9, 10, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 were analyzed. Patients had received HD-MTX-based chemotherapy, alone or with subsequent RT. Studies published in the English language and dealing with primary lymphoma of the brain and HD-MTX were identified using a MEDLINE search. We considered for analysis only patients without a known cause of immunosuppression, with
Drug efficacy (all eligible patients)
Twenty-one different CHT regimens were used. HD-MTX was used as mono-CHT (n = 102) or with other cytostatics (n = 186). No difference in survival was detected between these two groups of patients (p = 0.38) (Table 2). The MTX doses ranged from 1 to 8.4 g/m2. Patients receiving doses ≥3 g/m2 had a significant survival benefit compared with those receiving doses <3 g/m2 (p = 0.04) (Fig. 1 and Table 2). Of the 144 patients assessable for response who received the higher MTX dose, 92 (64%)
Discussion
Although exclusive RT was considered the standard treatment for PCNSL for some time, none of the irradiation parameters were clearly defined in either prospective trials or retrospective experience. These trials principally consisted of small series of patients treated with heterogeneous RT volumes, doses, and fractionation schedules. Some literature reviews have suggested that WB RT ≥40 Gy followed by a boost of ≥10 Gy to the TB was the most effective treatment in patients receiving exclusive
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