Chemotherapy in combination with WBXRT, or combined modality therapy, has been used to treat PCNSL for over two decades. Initially, chemotherapy regimens used to treat systemic NHL were employed. Systemic administration of CHOP or CHOD (with dexametha-sone), either before or after WBXRT, has been studied in two phase II and one randomized phase III trial.26 38 39 In the phase II, trials the reported median survivals of 10 and 13 months were no better than historical controls using WBXRT alone, and were associated with high toxicity and a 15% mortality. The randomized trial of WBXRT followed by CHOP or no further treatment showed no difference in failure-free or OS between the two arms, although the study was terminated early due to poor accrual. These data demonstrate that there is no role for CHOP-type therapy in the treatment of PCNSL.
The BBB is a unique obstacle to the successful treatment of brain tumors because high-molecular-weight or polar compounds cannot cross an intact BBB. Although there is partial disruption of the BBB in PCNSL, early successful treatment with corticosteroids effectively reconstitutes the barrier.40 Successful inroads to treating PCNSL include selection of drugs with physicochemical properties, such as lipid solubility and low molecular weight, which can permeate an intact BBB. One such drug is methotrexate (MTX), an antimetabolite that can penetrate the intact BBB when given intravenously at doses over 1 g/m2.41 High-dose MTX refers to systemically administered MTX, infused over 4-6 h, at doses higher than 1 g/m2 and usually over 3.5 g/m2, followed by folinic acid rescue. It plays a modest role in the treatment of systemic lymphoma, but has become the most important single agent in the treatment of PCNSL. The optimal schedule, dose, and regimen have not been established, but many mature phase II trials of combined modality therapy with MTX-based regimens have been published. These data are summarized in Table 58.1 and report higher median survivals than those seen with WBXRT alone. As is the case with phase II trials in general, single institutions report better outcomes than multi institutional trials. The reasons for these differences may be treatment-related, such as less familiarity with the chemotherapy protocol, but may also include referral bias, in that only a select number of patients are fit enough to travel to a specific center for experimental treatment.
Most of these trials used intrathecal and systemic chemotherapy to prevent leptomeningeal relapse or treat occult disease. Since intravenously infused, rapidly administered MTX in doses above 3 g/m2 can achieve cytotoxic CSF levels, it is unclear whether the addition of intrathecal chemotherapy is necessary. Furthermore complications arise from the placement of an Ommaya reservoir. A recent case-controlled retrospective study concluded that patients who received 3.5 g/m2 of MTX did not have improved disease control or survival with the additional administration of intrathecal chemotherapy.42 However, this conclusion did not apply to patients with overt positive CSF cytology.
Several large retrospective series have examined outcomes according to treatment.515 They provide long-term follow-up on a heterogeneously treated group of patients. One study of 466 patients in which only 6%, who had been treated with MTX-containing combined modality regimens. Those patients who received at least two cycles of chemotherapy had a median survival of 22 months, compared to 17 months for those treated with WBXRT alone. This difference was not significant. In the series from the International Extranodal Lymphoma Study Group (IELSG), about half of the patients were treated with high-dose MTX-containing regimens prior to WBXRT.
Results of combined modality treatment for PCNSL using MTX-based regimens
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