Primary Central Nervous System Lymphoma: Time to Ask the Question Howard A. Fine Neuro-Oncology Branch, National Cancer Institute, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD Journal of Clinical Oncology, Vol 20, Issue 24 (December), 2002: 4615-4617 PRIMARY CNS lymphoma (PCNSL) is defined as a diffuse lymphoma presenting in the brain or spinal cord in the absence of systemic lymphoma. Once considered a rare tumor, accounting for less than 1% of all systemic non-Hodgkin’s lymphomas (NHLs), the incidence of PCNSL has been increasing steadily since the 1970s. The rising incidence of PCNSL in the immunosuppressed patient population can be attributed to the spread of human immunodeficiency virus and to the more prevalent use of immunosuppressive agents. The reason for the apparent increased frequency of the disease in immunocompetent individuals, however, is less clear and may be due to better detection and diagnosis rather than a true increase in the incidence of the tumor. In either case, the number of patients with PCNSL who will be seen by oncologists over the next decade will likely continue to increase. To understand the specific issues related to the treatment of PCNSL, one must first appreciate the unique pathophysiology of the tumor. PCNSL most commonly presents as a single, contrast-enhancing lesion in the brain parenchyma, although other presentations can occur, such as a multifocal or diffuse intracerebral tumor, leptomeningeal lymphomatosis, intramedullary lymphoma, and ocular lymphoma, with or without CNS involvement. Regardless of the initial clinical presentation, the entire cranial-spinal axis is at risk for lymphomatous involvement given the tendency for PCNSL cells to spread along CSF pathways. Thus, therapies targeted to the tumor site alone are never curative. Another important consideration is that lymphoma cells rarely spread outside of the CNS, making systemic prophylaxis a less important consideration. The eye, however, is an important site for tumor spread, with intraorbital involvement occurring in approximately 5% of patients at presentation. As many as 15% to 20% of patients are at risk for ocular relapse, since most systemically administered chemotherapeutic agents do not achieve cytotoxic concentrations within the eye and standard whole-brain radiation fields (C2) do not involve the orbits. PCNSL also differs from systemic NHL in that it is extraordinarily sensitive to glucocorticoids, which often obscures the initial diagnosis or limits the interpretation of the efficacy of other concurrently administered therapies. Finally, the approach to the treatment of PCNSL differs from that for systemic NHL in that PCNSL resides within the exquisitely sensitive normal tissue of the brain, spinal cord, and eye and is protected by the microanatomical architecture of the cerebral endothelium, the blood-brain barrier. These anatomic constraints limit therapeutic options because of problems of inefficient drug delivery or fear of inducing neurotoxicity. The standard treatment for PCNSL has historically been whole-brain radiation therapy (WBRT), which results in complete radiographic responses in more than 80% of patients. Unfortunately, responses to WBRT are generally short-lived, and although systemic chemotherapy administered at the time of recurrence can induce marked radiographic responses, these responses tend to be transient. Thus, the overall median survival of immunocompetent patients with PCNSL treated with initial WBRT is less than 18 months from the time of diagnosis. In an attempt to improve on these results, and predicated on the chemotherapy-sensitive nature of systemic NHL, a number of investigators have explored the use of preradiation chemotherapy in patients with PCNSL. A number of different chemotherapy regimens have been utilized, with various ways of sequencing different radiation dose fractionation schemas. Individually, small trials do not allow one to draw definitive conclusions regarding optimal treatment regimens. Nevertheless, some conclusions can be safely inferred from these trials in aggregate. First, it appears that high-dose methotrexate is the most active single agent. Second, the overall survival of patients treated with initial chemotherapy, generally with a regimen that includes methotrexate followed by WBRT, seems to be significantly better than that of patients treated primarily with WBRT. Finally, if patients treated with chemotherapy and WBRT live long enough and are monitored closely enough, a significant percentage of such patients will develop clinically significant neurotoxicity. With this introduction, the article by DeAngelis describes the results of a multi-institutional phase II trial of a combined-modality treatment regimen for PCNSL, first piloted by the lead author at Memorial Sloan-Kettering Cancer Center (MSKCC). The regimen consists of moderately high-dose methotrexate (2.5 g/m2) followed by procarbazine (alternating every other cycle), vincristine, and intraventricular methotrexate, the latter delivered through an Ommaya reservoir. After five cycles of therapy, patients were treated with WBRT followed by two cycles of high-dose cytarabine. The investigators report a very high response rate to induction chemotherapy (94%) and median progression-free and overall survival times of 24 and 36.9 months, respectively. As promising as these results are, enthusiasm is tempered by the fact that 15% of patients experienced severe delayed neurotoxicity. This neurotoxicity was assessed clinically, so it is likely that more objective and quantitative testing would reveal subtle neurocognitive deficits in an even larger percentage of treated patients now and in the future. Unlike the more common reversible toxicities associated with treatment of systemic tumors, neurotoxicity is often permanent and progressive, severely impairing the patient’s quality of life. Patients treated with the DeAngelis/MSKCC regimen have survived so much longer than historical cohorts of patients treated with WBRT alone that a randomized trial comparing the two treatment regimens will likely never been done. Few physicians would feel comfortable withholding initial chemotherapy given the guaranteed poor prognosis after radiation alone. So, by default, does the MSKCC regimen become the standard treatment for PCNSL? Not yet. There are a number of reports demonstrating that other methotrexate-containing regimens used in this setting give response and survival rates similar to those for the MSKCC regimen. Of particular interest is a retrospective series from a single institution demonstrating that high-dose methotrexate alone resulted in a 100% response rate and an overall survival of greater than 30 months.On the basis of this report, the National Cancer Institute–sponsored New Approaches to Brain Tumor Therapy (NABTT) consortia conducted a prospective multi-institutional trial evaluating high-dose methotrexate (8 g/m2) in patients with newly diagnosed PCNSL with WBRT administered only at disease recurrence. A preliminary report of the data from that trial suggested results similar to the retrospective single-institution experience. A recent update of those data has demonstrated a 74% response rate to high-dose methotrexate alone and median progression-free and overall survival times of 12.8 and 22.8+ months, respectively (median survival has not yet been reached) . Although the progression-free survival rate seems to be lower than that reported by DeAngelis  none of the patients in the NABTT trial who achieved a complete response with methotrexate alone (12 of 23 patients, 52%) were irradiated unless they experienced disease recurrence. Thus, it is not surprising that the progression-free survival was lower than that reported in the DeAngelis trial. More importantly, it seems that the overall survival will be roughly similar to that seen with regimens that utilize radiation as part of the initial treatment. This suggests that delaying WBRT until tumor recurrence may be as effective as using it in the immediate postchemotherapy period. Without a randomized trial, it is impossible to know whether the MSKCC regimen is more neurotoxic than the NABTT regimen. However, preclinical and clinical data suggest that cranial radiation is a primary cause of late neurotoxicity. It is reasonable to speculate that the incidence and severity of neurotoxicity may be reduced if WBRT can be avoided or delayed. Given these arguments, I believe we have learned virtually all we can learn from phase II trials of PCNSL designed to evaluate some variation on the theme of conventional combination chemotherapy and radiation. I suggest that it is now time to ask a definitive clinical question. The range of clinical issues worthy of investigation include the role of WBRT, the long-term neurocognitive/neuroendocrine effects of chemotherapy with and without radiation, and the optimal drug regimen and method of administration, including intravenous, intra-arterial, and intra-CSF administration, blood-brain barrier disruption, and dose intensification. The DeAngelis et al and NABTT trials confirm the conclusions from the smaller phase II trials but do not definitively answer any new questions. These trials do, however, help to identify the most crucial and potentially answerable question, which is whether radiation is needed as part of initial treatment in patients who obtain a complete response to chemotherapy. I make this assertion both as a clinical investigator and a practicing neuro-oncologist often faced with patients with a newly diagnosed PCNSL. The question I struggle with the most is not whether I will treat with high-dose methotrexate alone or combined with other chemotherapeutic agents, but whether I should recommend to that patient WBRT immediately following completion of induction chemotherapy. A randomized phase III trial will be required to answer the question of immediate radiation versus radiation at the time of tumor recurrence. The need for WBRT, with its effects on patient survival, long-term neurotoxicity, and quality of life, is in my opinion the most pressing priority for a national collaborative effort. It is time to answer this question.