Flying Solo: Chemotherapy Without Radiation for Primary CNS Lymphoma

Primary CNS lymphoma (PCNSL) is an uncommon type of extranodal non-Hodgkin lymphoma confined to the brain, leptomeninges, or eyes. Although more than 90% of PCNSL tumors are classified histologically as diffuse large B-cell lymphoma, the survival of patients with PCNSL remains inferior to that observed in patients with diffuse large B-cell lymphoma occurring in other body sites. This may result from the unique biologic properties of PCNSL, the role of the blood brain barrier in limiting drug delivery to the tumor, and/or the lack of effective therapeutics. Consensus is lacking regarding the optimal induction and consolidative treatments for PCNSL. Although methotrexate is widely accepted as the foundation of induction chemotherapy for PCNSL, the optimal dose and schedule for this drug have not been defined. At the dose of 8 g/m, cytotoxic concentrations of methotrexate are achieved in CSF, obviating the need for intrathecal chemotherapy. Whole-brain radiation therapy (WBRT), although effective in achieving complete responses in the brain in most patients with PCNSL, might not improve survival over chemotherapy alone, does not adequately treat the entire craniospinal axis, and is associated with delayed neurotoxicity in most patients. The latter complication of WBRT may adversely impact cognition, functional status, and quality of life in patients otherwise successfully treated for PCNSL. Although reduced doses of WBRT might be associated with a lower incidence and severity of neurotoxicity in humans, this remains unproven and experimental studies have demonstrated that even single fractions of WBRT result in ablation of hippocampal neurogenesis and consequent neurotoxicity. The latter observation raises the question as to whether any dose of WBRT is safe, an important issue for a disease with survival measured in years. Despite these limitations, WBRT has been viewed historically as an integral component of either induction or consolidative therapy for PCNSL. This view has been challenged in recent years given that studies of chemotherapy alone suggest a diminished risk of neurotoxicity and promising efficacy in patients with PCNSL. In a long-term follow-up study of patients with PCNSL treated with chemotherapy alone and monitored with serial neuropsychological tests, cognitive function and quality of life were maintained. In the article that accompanies this editorial, Rubenstein et al report results from a cooperative group, multicenter, phase II clinical trial (CALGB 50202) of chemotherapy without WBRT in 44 patients with newly diagnosed PCNSL. Consensus guidelines were used to establish extent of disease and for response assessment and there were no eligibility restrictions with respect to age or sites of disease involvement (brain, leptomeninges, eyes). A sound scientific rationale was employed for the selection of the drugs in the induction and consolidation regimens employed in CALGB 50202. Each of the drugs selected for the methotrexate, temozolomide, and rituximab (MT-R) induction regimen had demonstrated safety and efficacy as a single agent in prior clinical studies in patients with either newly diagnosed or relapsed PCNSL. Etoposide and cytarabine (EA) had previously been combined as effective salvage therapy in a study of patients with relapsed PCNSL. Rubenstein et al demonstrated that this induction (MT-R) and consolidation (EA) regimen is feasible and safe in the multicenter setting with expected, reversible myelotoxicity associated primarily with consolidative EA therapy. There was one treatment-related death resulting from sepsis in a patient managed as an outpatient during EA consolidation prompting the authors to wisely advise that both the induction and consolidative components of this chemotherapy regimen should be administered on an inpatient basis with appropriate supportive care. Two thirds (66%) of the patients with PCNSL enrolled onto this trial achieved a complete response (CR) to induction MT-R, the primary end point of the study. This CR proportion is comparable or superior to that reported in other prospective, multicenter trials of induction chemotherapy for PCNSL. However, additional optimization of induction chemotherapy for PCNSL is a high priority, given that one-third of patients did not achieve CR, and these patients were excluded from proceeding to consolidative EA therapy. Moreover, it is worth considering whether patients who achieved a partial response after induction chemotherapy might have benefitted from EA. In a trial of myeloablative consolidative chemotherapy in patients with PCNSL, it was observed that patients who achieved a partial response after induction chemotherapy had similar, favorable outcomes after consolidative high-dose chemotherapy and autologous stem-cell transplantation compared with those who achieved a CR after induction chemotherapy. The 44 patients enrolled onto CALGB 50202 had a median progression-free survival of 4 years, and 59% of these patients were progression-free at 2 years. These are impressive achievements, comparable with or superior to results obtained in other prospective, multicenter trials with regimens that included WBRT as consolidative therapy. Median overall survival (OS) for the CALGB 50202 study had not been reached at the time of publication with a 4-year OS probability estimated at 65%. On the basis of these outcomes, it appears that omission of WBRT from the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 25 SEPTEMBER 1 2013