PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)

Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Therapy
  • Prognosis
    		•

    PCNSL is a rare form of NHL arising within and confined to the CNS. It was first described by Bailey (Bailey P. Intracranial sarcomatous tumors of leptomeningeal origin. Arch Surg. 1929;18:1359–1402) in 1929 as a perithelial sarcoma. Subsequent classifications have included reticulum cell sarcoma of the brain and microglioma. Improvements in histopathology and immunohistochemical techniques definitively established the lymphoid nature of PCNSL. PCNSL is of particular interest for several reasons. First, this tumor has increased in incidence over the past several decades. Therefore, although it remains relatively rare, it is an increasingly important differential diagnosis of intracranial mass lesions. Second, unlike many primary brain tumors, PCNSL is very responsive to treatment, and aggressive management may lead to prolonged remission or cure. Finally, the long-term consequences of aggressive therapy may result in significant neurologic dysfunction.

  • primary intraocular lymphoma (PIOL) initially involves the retina. Although PIOL is a rare malignancy, the incidence has dramatically increased in the past 15 years. Typical clinical manifestations include blurred vision and floaters. Ophthalmic examination reveals vitreitis and subretinal infiltrates. Diagnosis of PIOL can be difficult and requires neuroimaging, examination of the cerebrospinal fluid and/or vitreous. Treatment includes systemic chemotherapy and radiation with current regimens favoring the use of chemotherapy first. Vitreous involvement of the eye occurring prior to and during the course of CNS lymphoma has been noted in up to 25% of patients. Because PIOL has a nonspecific presentation, the differential diagnosis should include infectious and noninfectious causes presenting with vitreitis and/or subepithelial infiltration as well as paraneoplastic syndromes including CRMP-5 optic neuropathies. Given that therapy is long-term and has significant systemic and ocular complications, tissue diagnosis is important. Treatment of PIOL may include systemic chemotherapy in which high-dose methotrexate-based regimens are used as well as intraocular injections of methotrexate and rituximab. Cranial and ocular external-beam radiotherapy is being used less often todayref.
  • primary leptomeningeal lymphoma is rare and typically presents increased intracranial pressure, multifocal cranial neuropathies, or multilevel root involvement. Cerebrospinal fluid (CSF) should be obtained in all newly diagnosed patients. CSF evidence of PCNSL may also be a poor prognostic indicator. Tumor markers, including LDH isoenzymes, ß-glucuronidase, and ß2-microglobulin, may provide circumstantial evidence of leptomeningeal lymphoma. Immunocytochemical analysis and detection of Ig gene rearrangements by PCR have been used in the diagnosis of lymphomatous meningitis when routine cytologic evaluation is inconclusive. > 40% of patients have evidence of leptomeningeal dissemination, but concomitant clinical findings are uncommon
    • Epidemiology : incidence = 1:100000 per year. PCNSL accounts for  up to 6.6% of all primary malignant intracranial tumorsref and approximately 1.5% of all primary brain tumors in adult patients in large autopsy-based series. The incidence of PCNSLs has significantly increased over the last decade (Lantos PL, VandenBerg SR, Kleihues P: Tumours of the nervous system. Greenfield’s Neuropathology, vol 2, ed 6. Edited by DI Graham, PL Lantos. New York, Oxford University Press, 1997, pp 766–775), both in immunodepressed as well as in immunocompetent patients. More recent data suggest that the incidence among immunocompetent patients in the USA is increasing. Data from the National Cancer Institute Surveillance, Epidemiology, and End Result (SEER) database found a 3-fold increase in PCNSL between 1973-1975 and 1982-1984. Further analysis found a 10-fold or greater increase between 1973 and 1992. The incidence of ocular lymphoma has similarly increased by 1.5-fold. There has been a parallel rise in the incidence of all extranodal lymphomas, but the increase has been disproportionate in the brain and eye. This increased incidence is not explained by advances in neuroimaging or tumor diagnosis. As PCNSL primarily affects individuals aged > 60 years (the typical patient is between 55 and 70 years old; in AIDS-related PCNSL, the typical patient is younger (30-40 years old)), one possible explanation would be the general aging of the population; however, the data indicate an increase across all age groups. PCNSL is diagnosed in 1.6% to 9.0% of the HIV-infected populationref1, ref2 and is the second most common intracranial mass lesion. Prior to the introduction of HAART, the incidence of PCNSL in the HIV-infected population was continuing to rise. However, the impact of these new drug regimens on the CD4 count may result in a decline in PCNSL, as the susceptibility to PCNSL is inversely proportional to the CD4 countref
    Aetiologyref : an important risk factor for the development of PCNSL is primary or secondary immunodeficiency Pathogenesis : the pathogenesis of PCNSL in immunocompetent patients is unknown. T lymphocytes normally traffic in and out of the CNS; however, there is no normal traffic of B lymphocytes. Therefore, several different hypotheses have been proposed. There are no data to support or disprove any of these potential mechanisms. PCNSL may arise from a systemic lymphoma that seeds multiple organs, including the brain. The immune system has the capacity to find and eliminate the systemic tumor, but the brain, an immunologically privileged site, gives sanctuary to the malignant lymphocytes, thereby allowing tumor development. This seems unlikely, as there is no evidence of concomitant lymphoma in other immunologically privileged sites, such as the testes, concomitant with PCNSL. Another theory is that lymphocytes become trapped in the CNS after an inflammatory process and then undergo malignant transformation. However, inflammatory diseases almost exclusively attract T lymphocytes, and PCNSL is usually of B-cell origin. Also, the incidence of PCNSL is not increased in patients with inflammatory CNS diseases. Ongoing SHM, which is often observed in PCNSL, could be due to sustained AID expression in a fraction of cases and intraclonal V gene diversity may occur in other cases at an earlier phase of tumor clone expansion, when AID may have been expressed : on the other side internal Sm region deletions, imparing CSR and allowing only transcription of IgM and IgDref
    Symptoms & signs : most have had symptoms for only a few weeks prior to seeking medical attention. Cognitive and personality changes are the most common initial symptoms, reflecting the predilection of PCNSL to involve the frontal lobes, corpus callosum, and deep structures in close proximity to the lateral and third ventricles. PCNSL is multifocal in approximately 33% of patients and may present with any focal neurologic finding, such as hemiparesis or aphasia. Seizures are a presenting complaint in about 10% of patients, less frequent than glioma or brain metastasis. Age < 60 and an excellent performance status are the most important prognostic factors. About 15% of patients with PCNSL have ocular disease at presentation, while 50-80% of patients with isolated ocular lymphoma go on to develop parenchymal brain lymphoma. Ocular symptoms include blurred, cloudy vision, decreased visual acuity, or "floaters," but as many as half of affected patients are asymptomatic. Complete ophthalmologic evaluation, including slit lamp examination, is recommended in all patients. Diagnosis is often delayed in patients with isolated ocular lymphoma because of misdiagnosis as chronic vitreitis or uveitis. Systemic lymphoma is an uncommon finding in PCNSL, and there is disagreement as to whether a comprehensive systemic extent of disease evaluation is needed.
    Laboratory examinations : Therapy : Prognosis : the risk of relapse for patients treated with combined-modality therapy is about 50%. Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survivalref. Most recurrences are observed within 2 years of completing initial therapy, but relapses have been seen as late as 5 years. Patients with ocular or leptomeningeal disease at diagnosis have a higher likelihood of recurrence. Relapse primarily occurs in the brain at either the original or distant sites; however, leptomeningeal and ocular relapses are seen, and systemic relapse has been reported to account for as much as 10%. The prognosis at relapse is generally poor, but further treatment often results in transient remission. Prolonged survival is possible, and some patients continue to be sensitive to salvage therapy despite multiple relapses. Success has been reported using high-dose methotrexate (MTX) (even in patients previously treated with MTX), high-dose cytarabine, PCV (procarbazine, lomustine, and vincristine), and high-dose cyclophosphamide. RT is particularly effective for ocular relapse. Intensive chemotherapy with autologous PBSCT is standard therapy for patients with relapsed, chemosensitive, systemic NHL; this strategy has been used with some success for relapsed PCNSLref. However, patients previously treated with whole brain radiotherapy have a higher risk of neurologic toxicityref. II. Lymphomatous Meningitis: The Acute Lymphoblastic Leukemia Model
    CNS involvement among children with acute lymphoblastic leukemia (ALL) has historically been defined at most institutions by either the presence of >= 5 WBC/mlCSF associated with the presence of leukemic blasts (identified on a cytocentrifuged preparation) or the presence of a cranial nerve palsy on physical examinationref. Therapeutic approaches for both CNS prophylaxis and therapy have included the following : Despite these measures, there are patients who have been shown to still be at increased risk for CNS treatment failure. Mahmoud et alref challenged the conventional definition by showing that the presence of leukemic blast cells in the CSF, regardless of cell count, increased the risk of CNS relapse. In that study, all 351 children with newly diagnosed ALL were entered on a randomized trial in which each patient received intrathecal therapy throughout the first year. Patients who were considered at increased risk for treatment failure because of their clinical or cytogenetic features also received 18-Gy cranial irradiation and intrathecal chemotherapy 1 year from the remission date. Those with CNS disease at diagnosis (as defined by >= 5 leukocytes/mlCSF with leukemic blasts on a cytocentrifuged prep or by the presence of cranial nerve palsy on physical examination) received 24-Gy cranial irradiation and additional intrathecal chemotherapy. Patients were classified retrospectively into 3 CNS groups based on the CSF findings: 291 patients had CNS-1 status (no blasts in the CSF), 42 had CNS-2 status (blasts present with fewer than 5 leukocytes/ml), and 18 had CNS-3 status (>= 5 WBCs/mlCSF with leukemic blasts on a cytospin sample or cranial nerve palsy). The probability of an isolated CNS relapse in patients with CNS-2 status was higher than in those with CNS-1 status but was not different from that of patients with CNS-3 status. All CNS relapses occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, CNS-2 status was independently related to the risk of an isolated CNS relapse, suggesting that these patients require intensification of CNS-directed treatment early in the course of therapy. While a study of the former Pediatric Oncology Group confirmed this result (Lauer S, Shuster J, Kirchner P, et al. Prognostic significance of cerebrospinal fluid (CSF) lymphoblasts (LB) at diagnosis (dx) in children with acute lymphoblastic leukemia (ALL). Proc ASCO. 1994;13:317), studies by the former Children’s Cancer Group and the Dutch Childhood Leukemia Study Group did not find a significant difference in outcome between patients with or without a lower number of blasts in the CSFref1, ref2. These seemingly conflicting results may reflect differences in therapy. Patients who are HIV+ and develop a PCNSL are considered to have an extremely poor prognosis. In an attempt to provide a novel curative approach, Slobod et alref treated 2 HIV+ patients who presented with primary EBV-positive CNS lymphomas with hydroxyurea. This strategy was used based on in vitro studies of an EBV+ Burkitt’s lymphoma cell line, in which exposure to hydroxyurea resulted in loss of cytoplasmic EBV episomes and subsequent loss of malignant phenotype. On the basis of this observation, hydroxyurea was given to HIV+ patients who had EBV+ PCNSLs with objective clinical and radiographic responses, suggesting that antiviral approaches may have a role in these malignancies.
    CNS prophylaxis in adult ALL : the approaches most commonly used for CNS prophylaxis in adults are similar to those that have been used in children: These measures have reduced the rate of CNS relapse to < 5-10% from the > 30% rate reported when no prophylaxis is providedref. Gökbuget and Hoelzer reviewed the published data on CNS prophylaxis and found that a combination of all three of the above mentioned approaches resulted in the lowest incidence of isolated or combined CNS relapses (5%, range of 1-12%)ref1, ref2. Nevertheless, the use of cranial irradiation remains controversial. In the GMALL studies, a higher rate of CNS relapses was observed when cranial irradiation was either omitted or delayedref1, ref2. However, in Kantarjian et al’s study of the Hyper-CVAD regimen, which features high-dose systemic (MTX and cytarabine) and intrathecal therapy (no cranial irradiation) for CNS prophylaxis, the CNS relapse rate was very low (4%)ref.

    Secondary central nervous system lymphoma (SCNSL) : "secondary" lymphomatous involvement of the CNS was first recognized in the 19th century when Murchison described a tumor encroaching on the foramen magnum infiltrating the dura mater at autopsy (Murchison C. Case of ‘lymphadenoma’ of the lymphatic system, liver, lungs, heart and dura mater. Trans Pathol Soc Lond. 1870;21:372–389). The problem of extradural deposits was recognized later (Welch JE. Tumor of the neck showing unusual histologic features. Proc NY Pathol Soc. 1910;10:161; Guillan, Alajouanine, Perisson. Lymphosarcoma extradural metastique ayant determine une compression medullaire d’apparence primitive, d’evolution rapidement progressive; laminectomie; extirpation et radiotherapie; guerison. Bull Mem Soc Med Hop Paris. 1925;49:1057; Verda DJ. Malignant lymphomas of the spinal epidural space. Surg Clin N Am. 1944;24:1228–1244). By the middle of the 20th century, SCNSL had been the subject of many manuscripts (Davison C, Michaels JJ. Lymphosarcoma with involvement of the central nervous system. Arch Intern Med. 1930;45:908–925; Sparling HJ, Adams RD, Parker F. Involvement of the central nervous system by malignant lymphoma. Medicine. 1947;26:285–332; Williams HM, Diamond DH, Craver LF, Parsons H. Neurological complications of lymphomas and leukaemias. Springfield, IL: Charles C. Thomas; 1959), representing as closely as possible the natural history, with Sparling et al (Sparling HJ, Adams RD, Parker F. Involvement of the central nervous system by malignant lymphoma. Medicine. 1947;26:285–332) in 1947 reporting an autopsy incidence of only 1 in 118 cases. As the natural history of the lymphomas has been superseded by the clinical course (induced by partially successful therapy not targeting the CNS), survival of some subtypes has been prolonged. In the 1970s, incidence of SCNSL increased to approximately 10%ref1, ref2. A clear clinical picture, reflecting the outcome of therapy introduced in the late 1960s and early 1970s, emerges from a number of retrospective analyses from both single institutions and groupsref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, in which symptomatic disease occurred in 4-29%, depending on histology and extent of disease. The commonest features were headache, cranial nerve palsies, spinal cord compression, and altered mental state and affect. These problems usually arose within the context of poorly controlled lymphoma elsewhere, although the nervous system was occasionally an isolated site of recurrence. In the large majority of cases, the diagnosis was based on the history and the finding of abnormal cells on a cytospin of CSF. There was a strong association with bone marrow involvement; a correlation was also drawn between central nervous system lymphoma (CNSL) and involvement of the testis or paranasal sinuses. Likewise, close correlation was found between histological subtype and probability of the occurrence of CNSL; it was common with lymphoblastic lymphoma and Burkitt’s lymphoma and "Burkitt’s-like" lymphoma, to the extent that the next generation of treatment included CNS-targeted therapy.
    Prognosis : 20 years on, the demonstration of new prognostic factors and the introduction of the International Prognostic Index (IPI) have made it possible to identify more closely those patients for whom SCNSL is a high enough risk to warrant specific prophylactic therapy. At the M.D. Anderson Hospitalref, 24 of 605 patients with ‘large-cell’ or immunoblastic lymphoma developed CNS recurrence, with an actuarial risk at 1 year of 4.5%. In 5 cases, the recurrence was concurrent with systemic progression (within 40 days); in 7 others, it preceded systemic progression up to 6 months later. Involvement of > 1 extranodal site and elevated LDH at presentation were both independently predictive of CNS recurrence on multivariate analysis: if both were present, the actuarial risk was almost 20% at 1 year. However, despite intervention, with some apparent early benefit, only 1 of 24 patients was alive a year after recurrence. The risk of CNS recurrence according to the number of risk factors (age, LDH, albumin, number of extranodal sites, retroperitoneal involvement) in 1220 patients with high-grade NHLref :

    The Hovon multicenter groupref reviewed the risk of CNS recurrence in a trial testing the role of high-dose therapy with hematopoietic stem cell rescue, in patients responding "slowly" to 3 cycles of CHOP. 193 of 267 patients entered complete remission (CR). 10 patients (5%) developed SCNSL, 8 of them simultaneously with systemic progression. The risk was highest for patients with a high IPI score, but CNS recurrence occurred in all the risk groups. Survival data were not presented. Zinzani et alref reported an apparently higher incidence of isolated CNS recurrence in an unselected series (excluding Burkitt’s and lymphoblastic lymphoma) of patients with high-grade NHL (Kiel classification). 175 patients entered CR following therapy with MACOP-B or F MACHOP, both of which include modest doses of MTX intravenously but exclude intrathecal therapy. None had clinical evidence of CNS involvement at presentation. The minimum follow-up at the time of analysis was 3 years. 9 of 175 developed isolated CNS recurrence at a median of 3 months after CR had been documented. Multivariate analysis revealed advanced stage (III and IV) to be the only independent predictor of the likelihood of isolated CNS recurrence, although B symptoms, elevated LDH, and bone marrow involvement were all significant on univariate analysis. The outcome, whether the recurrence was leptomeningeal or parenchymal, was appalling, with all patients having died within 2 years because of CNS progression. In contrast, Haioun et alref reported the outcome for 1373 patients treated in a GELA study for patients with ‘aggressive’ NHL; lymphoblastic lymphoma and Burkitt’s lymphoma were excluded. CNS prophylaxis included intrathecal MTX with each cycle of systemic chemotherapy and 2 pulses of MTX 2 g/m2 with folinic acid rescue. There were 16 isolated CNS recurrences and a further 6 with progression at other sites. Initial multivariate analysis confirmed more than one extranodal site and elevated LDH to be independent risk factors predictive of CNS recurrence, each with a relative risk (RR) of 5. A further multivariate analysis (incorporating IPI score as a unique parameter, male gender, and B symptoms) was subsequently performed. IPI score remained the only parameter significantly associated with increased risk (low and low-intermediate versus high-intermediate and high, RR 7). Once again, the prognosis overall was poor, the median survival being 5 months and progressive disease being the predominant cause of death. A further study from the GELA (Tilly H, Coiffier B, Casasnovas O, et al. Survival advantage of ACVBP regimen over standard CHOP in the treatment of advanced aggressive non-Hodgkin’s lymphoma (NHL). The LNH 93-5 study [abstract]. Ann Oncol. 2002;13(suppl 2):082a) adds support for the benefit of CNS prophylaxis for this group of patients. Seven hundred eight adults aged 61-69 years with at least 1 adverse prognostic factor (IPI) were entered onto a trial comparing a relatively intensive chemotherapy program incorporating both intrathecal MTX and consolidation with systemic MTX, ifosphamide, and cytosine arabinoside, with standard CHOP. The CR rates were the same, despite a higher treatment-related mortality in the trial arm; overall survival, however, was better in the latter (P = .002). The frequency of CNS recurrence was also significantly lower in the trial arm (8 versus 25; P = .003). These results have been published in abstract form only to date. They are, however, supported by an earlier analysis from the M.D. Anderson Hospital in which outcome of patients receiving CNS prophylaxis in the form of intrathecal and intravenous MTX was better than that of matched historical controlsref. The largest body of data defining the extent of the problem at the end of the 20th century comes from the Norwegian Radium Hospital, Osloref. 2514 adults were treated for NHL according to protocols of the day, based on the histological subtype (Kiel) and the extent of disease at presentation. CNS prophylaxis was given to < 1%, 11%, and 83% of patients with low-grade, high-grade, and Burkitt’s or lymphoblastic lymphoma, respectively. The analysis addressed only the question of CNS progression, so 30 patients presenting with CNS involvement were excluded. Overall, the incidence reported for the histological groupings was very similar to that of other series. < 3% of those with "low-grade histology" developed SCNSL. Multivariate analysis confirmed B symptoms and involvement of bone marrow and skin as significant prognostic factors, with relative risks of 2.8, 2.8, and 3.7, respectively. The incidence for patients with Burkitt’s or lymphoblastic lymphoma was, in contrast, very high, being 24% overall, 78% in those not receiving prophylaxis, and 19% at 5 years in those that did. As in several other series, the SCNSL rate in ‘high-grade’ lymphoma was about 4%, the minority having received prophylaxis with intrathecal methotrexate about which no conclusions were drawn. Univariate analysis revealed a multitude of factors, including IPI and age-adjusted IPI, to predict for CNS recurrence. Testicular involvement in itself was not significant. Further analysis confirmed 5 factors to have an independent impact on CNS involvement: age, LDH, albumin, retroperitoneal nodes, and number of extranodal sites. Risk of central nervous system involvement :

    Although the hazard ratios are not identical, a general picture may be created by adding the risk factors and correlating increasing numbers with time-to-CNS involvement. Incidence of central nervous system (CNS) recurrence in patients with increased lactate dehydrogenase (LDH) and involvement of > 1 extranodal site (n = 93; dotted line) versus all other patients (n = 512; solid line)ref :

    The elimination of CNS involvement with lymphoma is a very important goal, even if it affects only a relatively small proportion of patients, most of whose overall survival will be dictated by uncontrolled disease elsewhere. It is a highly distressing complication, with potentially extensive morbidity which, when established, is very difficult to eliminate. Theoretically, therefore, a prophylactic strategy, analogous to that employed so successfully for ALL, is indicated. The risk of meningeal involvement in childhood lymphoblastic leukemia has been reduced from more than 50% to very low levels, after painstaking observations, identification of groups with different degrees of risk, and clinical trials to determine the most effective therapy with the lowest acceptable toxicity for each category. Most children now do not develop CNSL, nor do most have excessive long-term morbidity from the therapy. The first part of the process has been achieved for NHL. Follicular lymphoma and the other lymphocytic lymphomas have been shown to have < 1% probability of CNS infiltration, except when transformation has occurred: there can thus be no justification for prophylaxis. Burkitt’s lymphoma and lymphoblastic lymphoma (T and B) both have a high incidence of SCNSL: patients therefore now receive both intrathecal chemotherapy and high doses of MTX (and cytosine arabinoside in some instances) or cranial irradiation. As a consequence of this strategy, the incidence of CNS involvement is much reduced. For the remainder of the lymphomas, predominantly diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), there is still no uniformity of practice, which reflects the complexity of the situation and the fact that the data are open to differing interpretation. However, the picture may be clearer than it was 20 years ago. There is a recurring theme throughout the recent publications. CNS lymphoma is uncommon but not rare, and when it occurs, devastating. Patients presenting with a high IPI score, particularly reflecting the presence of a high LDH or involvement of more than one extranodal site, are at much higher risk of CNS involvement than the rest. Notwithstanding less impressive statistical proof of their individual significance, patients with testicular and sinus involvement are also at high risk. Some of the data reported above suggest that prophylaxis, with intrathecal therapy and systemic MTX, may reduce the risk. It could therefore be concluded that all patients with these histological subtypes of lymphoma (DLBCL and PTCL-NOS) should have the CNS evaluated by history, examination, and LP, and that those with a high IPI score, or high LDH and more than one extranodal site, should proceed to prophylaxis. There is a superficial attraction to designing a randomized trial to test the hypothesis. It might be difficult to execute. If it is difficult to select the appropriate group to receive CNS prophylaxis, it is equally difficult to determine what constitutes the best prophylaxis. Before the introduction of ‘high-dose’ MTX (Canellos GP, Skarin AT, Ervin T, Weinstein H. A chemotherapeutic approach to CNS lymphoma and leukaemia by the systemic administration of high doses of antimetabolites. In: Whitehouse JMA, Kay HEM, eds. CNS Complications of Malignant Disease. Macmillan Press; 1979:142-148) into combination chemotherapy, the only modalities available were intrathecal chemotherapy and irradiation. It may be clear from the above that intrathecal chemotherapy of short duration, while probably reducing the risk, does not eliminate it. Extrapolation from ALL makes this unsurprising: all treatments relying on intrathecal therapy alone demand much more prolonged treatment. Vital information about the efficacy of systemic MTX and the dose required in the absence of intrathecal therapy will come from the long follow-up analysis of the Southwestern Oncology Group-Eastern Oncology Group (SWOG-ECOG) study comparing CHOP with M-BACOD, MACOP-B, and PROMACE-CYTABOM, the trial arms including MTX and folinic acid rescue at a dose of 200 mg/m2, 400 mg/m2, and 1500 mg/m2, respectively. It may be anticipated that only the last dose might be effective. Further information accrued from clinical trials incorporating high-dose cytosine arabinoside may be helpful. Given at a dose of 2 g/m2, daily for 5 days, as part of the therapy for adults with ALL, cytosine arabinoside was as effective (compared with historical controls) as cranial irradiation in a small studyref.30 It would be foolhardy in the extreme to make didactic statements about optimal CNS prophylaxis: in the light of all that has gone before, recommendations can be made only on the basis of circumstantial evidence and must be seen as part of the best treatment of the disease overall. While none of the third-generation treatments above compared favorably with CHOP, perhaps a treatment for those with a high IPI score incorporating high-dose MTX (> 3 g/m2) and cytosine arabinoside (> 1 g/m2) might improve outcome. Were that perceived to be the case, a prospective evaluation of the strategy, particularly including long-term toxicity, would be required. Attention has been focused on reasons in favor of prophylaxis as opposed to against it. Emphasis has been placed on the unpleasant nature of the complication and the difficulty of eliminating it, once established. There are powerful clinical and economic reasons for not giving CNS-directed treatment if it can be avoided. Even though the long-term sequelae of prophylactic cranial irradiation are less worrying, there are enough data to suggest that high-dose systemic chemotherapy may be as effective and less toxic. It is, however, not without morbidity and mortality, which increase with the dose. Conversely, intrathecal therapy is inconvenient and not to be desired, has well-known toxicity, and is costly for both the patient and the hospital. All this must be taken into account in devising the best way to improve therapy, and demonstrate the improvement, while offering the individual the best advice. For future consideration: What emphasis should be given to the risk at the time of recurrent or progressive lymphoma? Do the same risk factors apply? Should more or less attention be directed to the problem? Should it be considered for only those still being treated with curative intent?

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