Novel therapeutic approaches that improve efficacy but avoid the deleterious neurocognitive effects of treatment, in particular those of standard-dose whole brain radiotherapy (WBRT), are needed in primary CNS lymphoma (PCNSL). The problem of radiation-induced delayed neurotoxicity is particularly significant for the approximate one-half of PCNSL patients older than 60 years (1
). While a preliminary report provided evidence that reduced dose whole brain irradiation (23.4 Gy) in conjunction with chemotherapy caused less neurotoxicity than standard dose WBRT (45 Gy) (2
), additional follow-up and validation of these results are needed and there remains a general concern that radiation-induced encephalopathy is a particularly undesirable and irreversible, treatment-associated morbidity.
High-dose methotrexate now represents the cornerstone of therapy in PCNSL (3
). In contrast to WBRT, treatment with high-dose methotrexate alone does not appear to frequently cause clinically severe neurocognitive impairment (4
). However, high-dose methotrexate monotherapy is rarely curative with at least 70% of patients exhibiting disease progression within 2 years (5
Our goal has been to develop a dose-intensive chemotherapeutic regimen that is tolerated by the majority of PCNSL patients, particularly during the first weeks after diagnosis when neurologic function and performance status are most compromised. For the past 10 years at the University of California, San Francisco (UCSF), newly diagnosed PCNSL patients have been treated with a novel, two-step immunochemotherapy program involving 4 months of induction therapy using intravenous high-dose methotrexate with oral temozolomide and intravenous rituximab (MT-R) followed by high-dose consolidation chemotherapy, without WBRT.
In the regimen, high-dose methotrexate with leucovorin rescue is given every 14 days for a planned 8 treatments. Standard dose intravenous rituximab is administered during the first 2 months of therapy, a window in which the blood-brain barrier is most often significantly compromised (7
) and we hypothesized would permit the delivery of rituximab to the tumor. Temozolomide has high relative lipophilicity with reliable CNS penetrance and a superior toxicity and health-related quality of life profile in brain tumor patients compared to procarbazine (8
). Temozolomide is active at relapse in PCNSL, both as monotherapy and in combination with rituximab (10
To attempt to potentiate long-term, progression-free survival after MT-R, PCNSL patients with at least stable disease received intensive consolidation chemotherapy with non-cross-resistant agents: 96-hour infusional etoposide plus high-dose, twice-daily cytarabine (EA)(13
). A similar combination of etoposide plus high-dose cytarabine was shown by Soussain et al. to be active as salvage therapy in recurrent/refractory primary and secondary CNS lymphoma, with 12 of 14 patients exhibiting responses, eight of which were complete responses (16
). Moreover 96-hour infusional etoposide has been incorporated within the EPOCH regimen, which is highly active in large cell lymphoma (17
), the most common histology to affect the CNS. A variety of reports have demonstrated the activity of etoposide in treating brain tumors, including lymphoid leukemia involving the CNS (19
). The use of etoposide has also been associated with a significant reduction in the risk of secondary CNS lymphoma, when given in combination with CHOP in patients with aggressive lymphoma (20
). The importance of high-dose cytarabine in PCNSL was also recently underscored in a randomized phase II study (21
Diffusion-weighted imaging (DWI) is a noninvasive MR imaging technique that produces in vivo images of brain based on differential rate of water diffusion or Brownian motion within the extracellular space. DWI is an essential tool to diagnose acute infarct in the brain due to its ability to detect early changes in altered water diffusion due to cellular damage. DWI has also been widely used in neuro-oncology to assess tumor biology. Specifically, the apparent diffusion coefficient (ADC) values derived from DWI have been shown to correlate with glioma grade (22
), tumor cellularity (24
), and treatment response (25
). A recent study also suggests that ADC values may be helpful in predicting clinical outcome in immunocompetent patients with primary CNS lymphoma (32
In this analysis, we describe the toxicity and long-term outcome of the first PCNSL patients to be treated with combination MT-R followed by EA at UCSF Medical Center, between 2001 and 2006. This study represents the first analysis of the survival of newly-diagnosed PCNSL patients to receive a dose-intensive consolidation chemotherapy regimen that involves neither autologous stem cell transplantation nor WBRT. This study also represents the first analysis of the role of etoposide as a component of consolidation in newly diagnosed patients with CNS lymphoma. Finally, we evaluated diffusion-weighted magnetic resonance imaging (DW-MRI) as a non-invasive tool to determine tumor minimal apparent diffusion coefficient (ADCmin) at diagnosis as a biomarker predictive of prognosis for PCNSL patients who receive MT-R induction therapy.