Management of Immunocompetent Patients With Primary Central Nervous System Lymphoma

Comprehensive Review

Management of Immunocompetent Patients With Primary Central Nervous System Lymphoma Emanuela Chimienti, Michele Spina, Emanuela Vaccher, Umberto Tirelli Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a non-Hodgkin lymphoma that arises within and is confined to the CNS. Recent data have suggested an increasing incidence in immunocompetent individuals, with a peak of incidence between 60 and 70 years of age. Patients with PCNSL present mostly with symptoms of increased intracranial pressure. The clinical management of these patients remains controversial, and the optimal treatment for patients with PCNSL has not yet been defined. Surgery, even if macroscopically radical, does not improve survival because of the multifocal and infiltrative nature of PCNSL; furthermore, the deep location of most of these tumors makes patients susceptible to serious and irreversible neurologic sequelae. Corticosteroids have a specific role in the treatment of patients with PCNSL, whose disease is sensitive to them as a chemotherapeutic agent. PCNSL is an extremely radiation-sensitive neoplasm; whole-brain radiation therapy plus corticosteroids was the first modality of treatment for patients with this neoplasm until 10 years ago, with a low cure rate and a high local recurrence rate. PCNSL is also a chemosensitive neoplasm; while the optimal choice, sequence, and combination of appropriate agents for efficacious treatment of patients with PCNSL has yet to be determined. An essential component of therapy must include an adequate drug delivery behind a normal blood-brain barrier. Methotrexate is the agent with the most proven activity in PCNSL. Combined-modality therapy has improved survival, but relapse is still common, and late neurologic toxicity is a significant complication, especially in older patients, who represent the majority of immunocompetent patients with PCNSL. Clinical Lymphoma & Myeloma, Vol. 9, No. 5, 353-364, 2009; DOI: 10.3816/CLM.2009.n.070 Keywords: Corticosteroids, Methotrexate, Neurotoxicity, Radiation therapy, Temozolomide, Topotecan

Introduction Primary central nervous system (CNS) lymphoma (PCNSL) is a non-Hodgkin lymphoma (NHL) that arises within and is confined to the CNS. For many years, this tumor was called microglioma, reticulum cell sarcoma, or perivascular sarcoma, but the lymphocytic origin of the malignant cell is now well established. Until recently, PCNSL has been a rare tumor, accounting for only < 5% of all primary CNS malignancies and 1%-2% of all lymphomas.1-3 Epidemiologic data have strongly suggested that PCNSL has increased in incidence over the past 10 to 15 years. Initially, this was thought to be due to the increasing incidence of AIDS and to the prolongation of survival of severely immunocompromised patients with AIDS because of highly active antiretroviral therapies; however, recent data suggest an increasing incidence in immunocompetent individuals as well.1-6 It is likely that at least a portion Division of Medical Oncology, National Cancer Institute, Aviano, Italy Submitted: Oct 8, 2008; Revised: Feb 13, 2009; Accepted: Feb 26, 2009 Address for correspondence: Umberto Tirelli, MD, Division of Medical Oncology, National Cancer Institute, Pedemontana Occidentale 12, 33081 Aviano (PN), Italy Fax: 39-0434-659531; e-mail: [email protected]

of this increase is due to improved neuroimaging and stereotactic neurosurgery, but other unknown factors are involved.5 Primary CNS lymphoma occurs in all age groups, but the peak of incidence is between 60 and 70 years of age in immunocompetent individuals (median age at diagnosis, 55 years). The male-tofemale ratio is 3:2.

Clinical Features Patients with PCNSL present mostly with symptoms of an intracranial mass lesion, consisting of signs of both motor and sensory focal deficits in about 50% of cases. Because this malignancy frequently involves the frontal lobes, changes in personality and level of alertness are common presenting symptoms. There are often signs and symptoms of increased intracranial pressure, such as headaches, vomiting, and papilledema. Seizures are less common than in patients with other CNS neoplasms, occurring in only 10% of patients as a presenting symptom because most PCNSL more often involves deep structures. Extrapyramidal syndrome or signs and symptoms of brain stem and cerebellum impairment are rarely present at the onset of the disease.7 Many lesions are periventricular; therefore, tumor cells can easily gain access to the cerebrospinal

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PCNSL in Immunocompetent Patients fluid (CSF). A study based on autopsy findings demonstrated a meningeal involvement in 100% of the cases; however, in the most numerous series, CSF examination demonstrated lymphomatous cells in less than half of the cases examined. It is probable that the development of new diagnostic techniques of molecular biology will reveal an increased percentage of positive examinations.7 The eye, a direct extension of the nervous system, is another site of multifocal disease in PCNSL. Typically, PCNSL involves the vitreous, retina, or choroid, but optic nerve infiltration could also occur. Symptoms of the eye involvement could precede CNS symptoms by months or years. At least 80% of patients with primary lymphoma of the eye will develop a cerebral lymphoma even after prolonged latency. It often presents itself as a nonspecific unilateral uveitis refractory to conventional ophthalmologic treatment, associated with floaters or campimeter deficit. Of all patients with PCNSL, 20% have ocular disease at diagnosis, mainly detected only by careful ophthalmologic examination. Primary leptomeningeal lymphoma in the absence of a brain lymphoma is rare, accounting for only 7% of cases of PCNSL, and primary spinal cord lymphoma is even less common.1,7

Diagnosis The computed tomography (CT)/magnetic resonance imaging (MRI) of PCNSL is quite distinctive, although not pathognomonic, and the diagnosis may be suspected on the basis of radiologic appearance alone. The mass is usually isodense or hyperdense on the precontrast CT scan, whereas it is isointense to hypointense on T2-weighted MRI images. After contrast administration, PCNSL densely and diffusely enhances on both CT and MRI.1 Enhancement might supply, in addition to diagnostic information, a prediction of the response to the chemotherapeutic treatment because it depends on the integrity of the blood-brain barrier (BBB); a lesion with less enhancement is usually associated with an intact BBB, which hampers the chemotherapeutic agents reaching the tumor.7 Importantly, edema is generally uncommon. The accumulation of fluorine-18 fluorodeoxyglucose (FDG) observed by positron emission tomography (PET) in PCNSL is similar to that seen in anaplastic gliomas and is significantly more prominent than in low-grade astrocytomas (P = .001); PCNSL, like gliomas, suppresses the metabolism of both contiguous and distant but functionally linked areas of the brain.8 FDG-PET displays a high sensitivity in PCNSL diagnosis, and it may be suitable for therapeutic monitoring.7,9 Recently, a retrospective analysis of FDG-PET/CT examinations collected from patients with PCNSL was published. A total of 42 PET/CT examinations were carried out in 25 patients with PCNSL. The sensitivity of PET/CT in detecting active disease in the brain was 87%, in the spine/nerves 80%, and in the eyes only 20%. The authors concluded that PET/ CT seems to be sensitive for the detection of viable intracerebral as well as spinal and peripheral nerve disease but not for the detection of ocular involvement.10 Despite these characteristics, quite distinctive for PCNSL, diagnosis requires histologic confirmation in immunocompetent patients; it can be obtained by performing a stereotactic biopsy but also by a lumbar puncture demonstrating leptomeningeal lymphoma.1 However, PET/CT could be useful in staging these patients

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even if the results of prospective studies using PET/CT both for staging and for the evaluation of response are warranted.

Molecular and Histologic Features Primary CNS lymphoma shows a morphology similar to that of systemic NHL, but these entities differ in their biologic and molecular behavior. Approximately 90% of PCNSLs are diffuse large B-cell lymphomas (DLBCLs); the remaining 10% are poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas.1 Recent studies have described these rare pathologic presentations, which are T-cell lesions and primary low-grade CNS lymphoma. The proportion of patients with T-cell PCNSL comprises about 2%-4% of cases; it was suggested that these forms might be associated with a better prognosis. However, in a large, retrospective study of 45 patients, the clinical presentation and outcome appear very similar to that of B-cell PCNSL.11 In the literature, small series or single case reports document another rare form of PCNSL: the primary low-grade CNS lymphoma. Among the lowgrade group, marginal zone lymphomas (mucosa-associated lymphoid tissue) represent the most common PCNSL. Pathologically, these tumors demonstrate CD20+CD3– small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly K light-chain restriction. It affects preferentially middle-aged women (female-to-male ratio, 4:1), presents classically as dural-based masses mimicking meningioma, and seems to be associated with favorable clinical behavior.12 Regarding tumorigenesis of PCNSL, the Epstein-Barr virus does not appear to be involved in the pathogenesis in the immunocompetent population in contrast to immunocompromised patients. The site of origin of the lymphoma cells as well as the biologic mechanisms involved in the neoplastic transformation of lymphocytes and in their intriguing confinement within the CNS during the course of the disease in most cases remain obscure.13 It is not clear whether the poor outcome of PCNSL compared with that of systemic lymphomas is attributable to the specific cerebral environments and/or reflects an intrinsic aggressive biologic behavior. BCL6 expression could predict improved survival, but at the moment, there is conflicting evidence from published studies.14,15 Recently, distinct gene expression profiles have been reported in systemic DLBCL and have been associated with opposite outcomes: those with expression patterns similar to germinal center B cells were associated with a significantly better overall outcome than those whose phenotypes resembled that of in vitro–activated peripheral blood cells (activated B cell–like; ABC).16,17 A recent study demonstrated a relatively homogeneous activated ABC immunophenotype of PCNSL, suggesting reasons for patients’ poor prognosis.15

Staging By definition, the diagnosis of PCNSL excludes the presence of other sites of localization outside the CNS. The tendency of PCNSL to remain confined to the CNS, and the lack of patients with systemic lymphoma presenting as a symptomatic cerebral mass, leads some authors to conclude that complete and intensive staging is unnecessary.7 Other authors instead report cases of

Emanuela Chimienti et al patients deemed affected by PCNSL in which complete staging has shown the presence of systemic lymphoma, which might involve the CNS in 5%-29% of cases.7,18-21 The initial workup should include physical examination; blood count and biochemical profile; HIV testing; craniospinal MRI scanning; cytologic evaluation and flow cytometry of CSF, if a lumbar puncture can be safely performed; a complete ophthalmology evaluation; CT scanning of the thorax, abdomen, and pelvis; and a bone marrow biopsy with aspirate (Ann Arbor level of evidence IIA).7,18,19,22 The standard staging system used for PCNSL is the same as that proposed for Hodgkin disease at the Ann Arbor Conference in 1971. These extranodal lymphomas are considered stage IE disease.7

Management The clinical management of these patients remains controversial, and the optimal treatment for patients with PCNSL has not yet been defined.

Role of Surgery Surgery, even if macroscopically radical, does not improve survival because of the multifocal and infiltrative nature of PCNSL; furthermore, the deep location of most of these tumors makes patients susceptible to serious and irreversible neurologic sequelae. Now there is a great consensus that aggressive and decompressive surgery with total or partial macroscopic tumor removal is ineffective for patients with PCNSL; in fact, the median survival of patients treated only with supportive care ranges from 1.8 months to 3.3 months, and that of patients treated with surgical resection ranges from 3.3 months to 5 months. Therefore, surgery today retains a defined role only in diagnostic sampling. However, because of the great incidence of serious neurologic damage, the traditional craniotomy has been replaced by the safer stereotactic biopsy, which provides suitable samples, with a complication incidence of about 2%.1

First-line Treatment With Corticosteroids Corticosteroids play a critical role in the management of neurologic symptoms in any patient with an intracranial mass; this is true for patients with PCNSL as well. However, corticosteroids have an additional specific role in the treatment of patients with PCNSL, whose disease is sensitive to them as a chemotherapeutic agent. Corticosteroids can cause cell lysis and documented radiographic regression of PCNSL in ≥ 40% of patients. This is due not only to the reduction of the perilesional edema but much more to the direct cytotoxic and oncolytic effect of corticosteroids.1,23 Despite this evidence, corticosteroid use should be avoided until a histologic confirmation of the diagnosis can be reached.

Radiation Therapy Alone or in Combination With Chemotherapy Primary CNS lymphoma is an extremely radiation-sensitive neoplasm; therefore, whole-brain radiation therapy (WBRT; RT) plus corticosteroids have been the primary modality of treatment for patients with this neoplasm for the past 25 years, yielding median survival times of only 12-18 months.1,24 The Radiation Therapy Oncology Group has reported a local control rate of 39%

in PCNSL, with 79% of recurrences even in the regions treated with 60 Gy, and a median survival of only 11.6 months from the beginning of RT and 12 months from the diagnosis. In this report, only 15% of the patients were alive without evidence of disease after 54 months of follow-up.20 In PCNSL, the optimal field and doses have not been identified. In 1967, a minimum dose of 30 Gy was recommended, and in 1983, a minimum dose of 35 Gy was recommended.24 Murray et al, in 1986, noted a threshold dose of ≥ 50 Gy; they reviewed 86 series in the literature, and out of 198 patients in whom the RT doses to tumor were specified, they noted a 5-year survival rate of 42.3% in 54 patients who received ≥ 50 Gy, while in 154 patients who received < 50 Gy, the survival rate was 12.8%.25 Pollack et al reported on 17 patients treated between 1976 and 1986; they observed a 65% 5-year survival rate for patients who received 40-50 Gy WBRT compared with 28% for those who received < 40 Gy.26 The largest retrospective study of RT in PCNSL comes from Japan, where 119 patients with PCNSL treated between 1970 and 1988 were reviewed. The series included patients aged 1-80 years, with a Karnofsky performance status (PS) of 10%-100% and a positive cytology in 24% of the patients. Out of 101 patients treated with RT, 8% received < 40 Gy, 29% received 40-50 Gy, and 14% received > 60 Gy. No improved survival was observed with doses > 40 Gy.21 The dose administered to the tumor bed is also a determinant in therapeutic outcome; patients having received > 50 Gy to the tumor bed had a longer survival in comparison with patients treated with a lesser dose. Radiation therapy alone in the treatment of patients with PCNSL has a low cure rate with a high local recurrence rate. Certainly, doses above 40-50 Gy do not appear to increase survival, but they do increase toxicity.24 A review of 50 series of 1180 patients with PCNSL published between 1980 and 1995 was performed by Reni et al, who evaluated the effect of age, treatment strategy, radiation fields and doses, and systemic and intrathecal chemotherapy on survival. Univariate analysis showed a longer survival in patients aged < 60 years, in patients treated with > 40 Gy to the whole brain, in patients receiving > 50 Gy to the tumor bed after a WBRT dose of > 40 Gy, and in patients receiving combined treatment as opposed to RT or chemotherapy alone. Multivariate analysis confirmed the independent prognostic value of WBRT doses of > 40 Gy.27 There are no prospective trials providing therapeutic results obtained with chemotherapy followed by RT versus the inverse sequence. Experimental and clinical data support the use of chemotherapy-RT as the optimal sequence.27,28 In combined treatment, RT doses should be decided on the basis of response to primary chemotherapy. WBRT with 30-36 Gy followed by a tumor-bed boost of 10-15 Gy may be advisable in patients with residual disease, whereas WBRT with 30 Gy, which may be followed by a tumor-bed boost to reach 36 Gy, appears suitable for patients in complete remission after chemotherapy.7 After recurrence, the tumor usually becomes refractory to further treatment; therefore, new approaches to disease management are required.29

Chemotherapy and Combined-Modality Treatment The use of chemotherapy began in the mid-1970s after methotrexate (MTX) was shown to be successful in the treatment of

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PCNSL in Immunocompetent Patients patients with systemic lymphoma involving the CNS.30 PCNSL is a chemosensitive neoplasm; however, the failure of many regimens, particularly those adapted from therapy for systemic lymphoma, could be attributed to the fact that none of the agents or dosages used permit drug penetration through an intact BBB. While the optimal choice, sequence, and combination of appropriate agents for efficacious treatment of patients with PCNSL has not yet been determined because an essential component of therapy must include adequate drug delivery behind a normal BBB, where microscopic disease always resides. Methotrexate is the agent with the most proven activity in PCNSL. When given intravenously, it penetrates an intact BBB and achieves parenchymal levels proportional to peak serum levels when used at doses > 1 g/m2. When administrated by the intraventricular or intrathecal route, there is a good distribution throughout the CSF but little penetration into the brain parenchyma. High-dose intravenous (I.V.) MTX (3-8 g/m2) alone or in combination with other agents or radiation can prolong survival in immunocompetent patients with PCNSL compared with RT alone or with regimens that do not contain MTX. The major acute toxicities associated with high-dose MTX are myelosuppression, mucositis, and renal failure. The hematologic and mucosal toxicity can be prevented by commencing leucovorin rescue within 24 hours of the dose, and the renal toxicity, resulting from the deposition of crystals of the drug in the proximal renal tubule, can be prevented by the administration of fluids and by urine alkalinization with sodium bicarbonate. Penetration of MTX into the CSF after I.V. administration is dose dependent; concentrations of 10 μmol/L can be achieved in the CSF with a systemic dose of 3.5 g/m2. Although these doses produce cytotoxic effects for most lymphoma cell lines, intrathecal administration of the drug produces levels 10-fold higher. Methotrexate is the most effective drug in the treatment of patients with PCNSL, although leukoencephalopathy can develop after its use, ranging from asymptomatic white matter changes observed on MRI to a severe and progressive dementia, destroying the patient’s quality of life. Moreover, the risk of developing leukoencephalopathy increases when MTX is given with cranial irradiation and when it is administered to elderly patients.7 The use of cyclophosphamide in the treatment of patients with PCNSL is limited because of its water solubility; it only partially permeates an intact BBB. The amount of a drug that crosses the BBB and reaches the tumor is proportional to its peak serum concentration, which is a function of dose and schedule. Based on these pharmacologic principles, a possible approach to the nonoptimal penetration of cyclophosphamide is to increase the peak serum concentrations and thus the dose. The maximum tolerated dose of cyclophosphamide, when used in combination with doxorubicin, is 4 g/m2. The toxicity reported is mainly hematologic; one third of the patients develop grade 2 mucositis. Another drug with significant activity against lymphoma is cytarabine (Ara-C), which has a short half-life, with metabolism occurring through deamination by cytidine deaminase, a ubiquitous enzyme with high levels in the liver, kidney, and gut. However, there are only low levels of this enzyme in the CNS, so Ara-C penetrates the CNS but is degraded at very low rates, leading to a long half-life in the CNS. Moreover, Ara-C attains therapeutic concentrations

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in CSF for > 48 hours, offering the advantage of treating both brain parenchyma and leptomeningeal disease. Therapeutic levels of Ara-C may be achieved only with high-dose therapy. Another important feature of Ara-C is that therapeutic levels are detected in both the aqueous and vitreous humors 90 minutes after I.V. administration, suggesting that this drug could also prove useful to treat malignant diffusion to the eye.29 Neurotoxicity, characterized by cerebellar dysfunction, irreversible in a small number of cases, can develop; in addition, peripheral neuropathy has been described. Several chemotherapy regimens have been used in the treatment of patients with PCNSL, for which the experience of each single regimen is limited. Chemotherapy regimens reported for PCNSL can be divided into 2 groups: regimens with no drug passing the BBB, usually CHOP (cyclophosphamide/doxorubicin/vincristine/ prednisone) or CHOP-derived regimens and regimens with drugs crossing the BBB. Many studies have used CHOP or CHOP-like regimens for the treatment of patients with PCNSL, most yielding disappointing results, with median and long-term survival not different from those of patients treated with RT alone.28,31 To date, only 1 prospective, randomized phase III trial comparing RT alone versus RT plus chemotherapy has been reported. After surgery, patients were randomized to RT alone (40 Gy to the whole brain followed by a 14-Gy boost to the tumor bed plus 2-cm tumor margins) or to the same RT followed by 6 cycles of CHOP given at 3-week intervals. Between 1988 and 1995, 53 patients were randomized (15 to RT and 38 to RT plus chemotherapy), and the trial closed earlier than planned because of poor accrual. There was no evidence of a benefit from RT/CHOP with respect to overall survival (OS) after adjustment for prognostic factors. Moreover, CHOP chemotherapy was associated with substantial toxicity.32 Pilot studies using regimens with drugs crossing the BBB, such as high-dose MTX or Ara-C, might improve the outcome of patients with PCNSL compared with RT alone or combined with CHOP or CHOP-derived regimens.33 This has been further confirmed by the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) study, where prognostic factors for survival and late neurotoxicity were analyzed for 226 patients with PCNSL. In a univariate analysis, age > 60 years, PS, CSF protein level > 0.6 g/L, involvement of corpus callosum or subcortical gray structures, detectable lymphoma cells in CSF, and increased serum lactate dehydrogenase (LDH), were significantly correlated with poor survival. Treatment with chemotherapy versus RT alone, high-dose MTX, and Ara-C was correlated with better survival. Using the Cox model, age, PS, and CSF protein levels were independently correlated with survival. After adjustment for these factors, treatment with a high-dose MTX–containing regimen remained the only treatment-related factor independently correlated with survival.28 The results of a critical review of the literature performed by Reni et al confirm the prognostic value of age and support the use of systemic chemotherapy consisting of high-dose MTX and intrathecal drug administration followed by 41-50 Gy to the whole brain and > 50 Gy to the tumor bed as successful treatment for patients with PCNSL.27 Abrey et al treated 57 patients with PCNSL with 5 cycles of high-dose MTX 3.5 g/m2, procarbazine 100 mg/m2/day, and vincristine 1.4 mg/m2 as a pre-RT regimen, obtaining an objective response rate of 90% (56% of the patients achieved a complete

Emanuela Chimienti et al response [CR], while 33% achieved a partial response [PR], with an estimated median OS of 60 months).34 Chemotherapy was followed by WBRT to a total dose of 45 Gy. WBRT was deferred routinely in all patients aged > 60 years who were diagnosed during or after 1995; in addition, 4 patients aged < 60 years refused initial therapy with WBRT in an effort to minimize the cognitive effect of treatment. Therefore, 26 patients were treated with chemotherapy alone. The overall objective response rate (CR + PR) after the completion of RT was 94%. Recently, an update of these results has confirmed an excellent median survival of 51 months.35 The median survival of patients aged ≥ 60 years was 29 months regardless of whether they received WBRT, and the median survival of patients aged < 60 years at diagnosis has not been reached. Thirty percent of the patients developed treatment-related neurotoxicity; the risk was highest in patients aged > 60 years who received WBRT as part of initial therapy. However, 26% of patients aged < 60 years who received WBRT also developed cognitive impairment or dementia. In total, 46% of the patients who received WBRT as part of initial or salvage therapy developed treatment-related neurotoxicity. Guha-Thakurta et al treated 31 immunocompetent patients with PCNSL using I.V. MTX without RT: 65% of the patients achieved a CR, and 35% achieved a PR, with a median survival of 30.4 months.36 The 2-year survival was 63% for all the patients and 90% for those who achieved CRs. Of great importance, these patients did not show any clinical or MRI signs of encephalopathy, with a preservation of clinical cognition and memory. Sarazin et al treated patients with PCNSL between 1989 and 1993 using 3 different regimens: 1 group (13 patients) received preRT systemic and intrathecal MTX, RT, and 3 courses of post-RT chemotherapy with thiotepa and procarbazine; the second group (4 patients) received a similar chemotherapy regimen after RT and without intrathecal MTX; the third group (5 elderly patients) received chemotherapy alone.37 In the first group, all but 1 patient experienced complete remission after RT, and after a median follow-up of 27 months, 62% of the patients were alive. In the second group, all patients were in complete remission after RT, but meningeal recurrence occurred in all but 1 patient. In the last group, all but 1 patient had a CR to chemotherapy: 2 patients died of recurrent tumor, 2 are still alive at 11 and 21 months after diagnosis, 1 being alive after salvage therapy. This study suggests that combined treatment with RT and chemotherapy is useful in PCNSL and that chemotherapy alone is sometimes of value in patients to whom RT cannot be administered, such as elderly patients. High-dose MTX is proven to be efficacious and a relatively safe treatment for patients with PCNSL, but infusion schedules differ among published studies, and no detailed investigation of the relationship between the infusion schedule and therapeutic effects has been published except for the study by Hiraga et al, who treated 29 immunocompetent patients with PCNSL using high-dose MTX and investigated the correlation of infusion schedules with MTX penetration into CSF as well as tumor response and survival.38 They administered 100 mg/kg (equivalent to the 3.5 g/m2) on either a rapid (3-hour) or regular (6-hour) infusion schedule for 2 or 3 cycles, achieving a CR in 93.8% of the patients receiving the rapid-schedule infusion and in 58.3% of those receiving the regular infusion. Rapid infusion significantly increased levels of

MTX in the CSF and resulted in significant tumor volume reduction, higher than that observed in the regular-infusion group. The median survival time of all patients treated with MTX plus RT was 39.3 months. The time-course curve of MTX concentration in CSF was significantly elevated, and the total area under the curve was significantly larger for the rapid-infusion group compared with the regular-infusion group. These findings indicate that the increased exposure to MTX resulting from rapid infusion correlates with an intensified tumor response. Korfel et al treated 11 immunocompetent patients with PCNSL between 1994 and 1997 with a regimen composed of carmustine 80 mg/m2 day 1, MTX 1.5 g/m2 over 24 hours day 2, procarbazine 100 mg/m2 orally days 1-8, and dexamethasone 24 mg orally days 1-14 for 3 courses; patients with positive cytology received intrathecal therapy.39 Some patients received RT also. At the end of chemotherapy, CR was achieved in 6 patients, and PR was achieved in 2 patients. Moreover, it is of great importance that 2 elderly patients had CRs lasting for 40 months and 37 months, respectively. Dent et al added intrathecal chemotherapy (MTX day 1 and AraC day 8) to PROMACE (cyclophosphamide/doxorubicin/etoposide/MTX/folinic acid/prednisone) with or without MOPP (mechlorethamine/vincristine/procarbazine/prednisone) for the treatment of 7 patients with PCNSL, achieving CR in 6 patients, with a median survival of 100 weeks.40 Bessel et al treated 34 patients with PCNSL using 3 different regimens of chemotherapy: they treated 12 patients with BVAM (carmustine/vincristine/Ara-C/MTX), 17 patients with CHOD (cyclophosphamide/doxorubicin/vincristine/dexamethasone) and BVAM, and 5 patients with intensified CHOD/BVAM.41 Twenty patients received RT to the whole brain as well. At the end of chemotherapy, CRs were achieved in 63% of the patients receiving BVAM and in 67% of the patients receiving CHOD/BVAM. More toxicity occurred with CHOD/BVAM. The 5-year actuarial probability of survival of all 34 patients was 33%, with only 1 recurrence after 2 years. Blay et al used a protocol composed of 5 courses of chemotherapy, named C5R, plus RT to treat immunocompetent patients with PCNSL.42 The chemotherapy regimen was derived from the Lymphome Malins B regimens used for pediatric B lymphomas and consisted of 1 course of COP (I.V. cyclophosphamide, I.V. vincristine, intrathecal MTX, intrathecal hydrocortisone, and I.V. methylprednisolone ), followed 7 days afterward by the first course of COPADEM (I.V. vincristine, I.V. high-dose MTX, I.V. folinic acid, I.V. doxorubicin, I.V. cyclophosphamide, I.V. methylprednisolone, and intrathecal MTX plus intrathecal hydrocortisone). The second course of COPADEM and 2 courses of the CYM regimen (I.V. high-dose MTX, I.V. folinic acid, I.V. Ara-C, and intrathecal MTX, intrathecal Ara-C, and intrathecal hydrocortisone) were administered at 21-day intervals. RT was started 21-35 days after the last course of CYM. At the end of chemotherapy, CR was achieved in 56% of the patients and PR was achieved in 16%. Myelosuppression was the most frequent side effect. With a median follow-up of 24 months, the projected survival of the group at 2 and 5 years is 70% and 56%, respectively. In the selected group of patients aged < 61 years and with an International Prognostic Index < 4, the projected OS rates at 2 and 5 years are 88% and 70%, respectively. The major concern with this regimen was the risk of

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PCNSL in Immunocompetent Patients leukoencephalopathy, but at 5 years’ follow-up, the authors have found no patients experiencing neurologic complications, as evaluated by frequent physical, CT scan, and MRI examination. Brada et al treated 31 immunocompetent patients with PCNSL using the chemotherapy regimen MACOP-B (cyclophosphamide/ doxorubicin/methotrexate/leucovorin/vincristine/bleomycin) and the modified regimen MACOP, consisting of I.V. cyclophosphamide, doxorubicin, MTX, folinic acid, and vincristine followed by RT (whole-brain and boost).43 The MACOP-B regimen was modified because of the observation of early BBB repair after chemotherapy administration. Patients obtained an overall CR rate of 69% after chemotherapy plus RT; at a median follow-up of 24 months, median survival was 23 months, and the 5-year survival rate was 34%. All of the long-term survivors have returned to normal life and those of working age to full-time employment, without cognitive impairment, while patients with cognitive dysfunction before treatment remained disabled. Brada et al treated, some years before, 10 patients with PCNSL using MACOP-B followed by WBRT, obtaining a median survival of only 14 months.44 Recently, Ferreri et al treated 41 immunocompetent patients with PCNSL with a chemotherapy regimen named MATILDE (MTX/Ara-C/idarubicin/thiotepa) for 3 cycles at 21-day intervals, followed by WBRT (30 Gy in patients with complete remission, 36 Gy in those with partial remission, and 45 Gy in patients with stable or progressive disease, followed by a 9-Gy tumor-bed boost).45 The overall response rate after MATILDE was 76%. At the end of chemotherapy, with or without radiation therapy, 23 patients (56%) had complete remission, and 11 had partial remission (response rate, 83%). A total of 24 patients experienced progressive disease (PD; 3-year failure-free survival [FFS], 43% ± 8%). Twenty-one (88%) treatment failures occurred during the first 2 years of follow-up. The 5-year OS rate was 41% ± 7%. The authors showed that MATILDE followed by WBRT is a feasible and active strategy for patients aged ≤ 70 years with PCNSL. Moreover, this regimen allows successful treatment of patients with meningeal disease without intrathecal drug delivery. In an effort to improve the CR rate and reduce the toxicity of RT, Shah et al treated 30 newly diagnosed patients with PCNSL with induction chemotherapy (MTX, procarbazine, vincristine) along with rituximab (R-MPV).46 If a CR was observed after 5 courses of R-MPV, then the patients went on to receive reduced-dose WBRT (23.4 Gy). If a PR was observed, patients received 2 additional courses of R-MPV and were re-evaluated. A CR after 7 courses of chemotherapy also led to low-dose WBRT, but evidence of a response < CR led to full-dose WBRT (45 Gy). After completion of WBRT, 2 courses of Ara-C were administered at 3 g\m2\day for 2 days. In total, 23 of the enrolled patients (77%) achieved a CR by the completion of all planned therapy. After completion of all chemotherapy, 27 patients were assessed for response: 21 achieved a CR (78%), and 4 achieved a PR (15%). Of 21 patients with a CR, 19 patients received reduced-dose WBRT at 23.4 Gy, and 2 of the 4 patients with a PR received full-dose WBRT at 45 Gy and achieved CR. The addition of rituximab resulted in significant neutropenia requiring routine use of growth factor support, but no other unexpected toxicities were observed. Among the two thirds of patients who were treated with a reduced-dose WBRT, treatment-

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related neurotoxicity was not observed, with a median follow-up of 37 months. Moreover, disease control in this patient cohort was excellent, with only 26% of the patients experiencing progression. It is not clear whether consolidation treatment is necessary for patients who achieve a CR after induction high-dose MTX–based chemotherapy. To assess the effect of consolidation treatment, Ekenel et al retrospectively analyzed 122 patients who achieved a CR after initial MTX-based chemotherapy.47 Consolidation strategies were as follows: no consolidation treatment, WBRT or highdose Ara-C, or both. With a median follow-up of 60 months, FFS was longer in patients who received WBRT plus high-dose Ara-C as consolidation treatment, but there was no difference in OS among the different consolidation strategies. However, WBRT alone or in combination with high-dose Ara-C was associated with a higher rate of neurotoxicity. This study suggested that consolidation treatment with WBRT, high-dose Ara-C, or both does not appear to improve survival in patients who have achieved a CR with induction MTX-based therapy. Therefore, MTX 3 g/m2 at least should be considered the gold-standard regimen for the management of PCNSL (Ann Arbor level of evidence IIA). Most likely, WBRT could be omitted in elderly patients in CR after 3 cycles of highdose MTX (Ann Arbor level of evidence IIA). Recently, Ferreri et al reported the primary results of the first randomized phase II trial of chemotherapy with high-dose MTX alone or with high-dose Ara-C followed by WBRT for 79 patients with PCNSL.48 Complete response rates after chemotherapy were 18% and 46%, while overall response rates were 40% and 69%, respectively, for patients treated with MTX alone and with MTX and Ara-C. After conclusion of the entire up-front treatment, CR rates were 28% and 64%, respectively, for patients treated with MTX alone and with Ara-C. This study suggests that the addition of Ara-C to MTX is associated with significantly better outcome and acceptable toxicity. Results of the main studies are shown in Table 1.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation High-dose chemotherapy with autologous peripheral blood stem cell transplantation (autoPBSCT) has been used as a strategy to intensify the dose of chemotherapy given to patients with newly diagnosed or relapsed PCNSL or to replace consolidation WBRT to avoid treatment-related neurotoxicity. There have been 2 small autoPBSCT phase II trials in patients with newly diagnosed PCNSL. Abrey et al treated 28 patients with intensive MTX and Ara-C, followed by BEAM (carmustine/etoposide/Ara-C/melphalan) consolidation chemotherapy. Fifty percent of the patients had chemosensitive disease; a significant proportion relapsed after transplantation. Eighteen percent of the patients remained in remission at a median of 26 months after transplantation.49 In a recently reported multicenter trial, 30 patients with newly diagnosed PCNSL aged < 65 years were treated with induction chemotherapy (a combination of MTX, thiotepa, and Ara-C) followed by high-dose chemotherapy with carmustine and thiotepa and hyperfractionated RT. The complete remission rate was 65%, and 5-year OS rates of 87% and 69%, respectively, were observed for patients who received autoPBSCT and for all enrolled patients.50

Emanuela Chimienti et al Table 1 Combined-Modality Treatment in Primary Central Nervous System Lymphoma Regimen

Number of Patients

CR/OR Rate

Median OS, Months

High-Dose MTX, Procarbazine, and Vincristine for 5 Courses Plus WBRT (45 Gy)34,35

57

OR, 94%

51

31

CR, 69%

23

41

OR, 76%

15

30

OR, 93%

Not reached

79

OR, 40% with MTX alone; 69% with MTX plus Ara-C

Not reached

MACOP-B (MACOP) Plus

WBRT43

MATILDE for 3 Courses Plus WBRT45 R-MPV for 5 (if CR) or 7 Courses (if PR) Plus WBRT Plus Ara-C for 2

Courses46

High-Dose MTX With or Without High-Dose Ara-C Plus WBRT48

Abbreviations: Ara-C = cytarabine; CR = complete response; MACOP = cyclophosphamide/doxorubicin/methotrexate/leucovorin/vincristine; MACOP-B = cyclophosphamide/doxorubicin/ methotrexate/leucovorin/vincristine/bleomycin; MATILDE = methotrexate/cytarabine/idarubicin/thiotepa; MTX = methotrexate; OR = overall response; OS = overall survival; PR = partial response; R-MPV = methotrexate/procarbazine/vincristine plus rituximab; WBRT = whole-brain radiation therapy

Other studies of high-dose therapy and autoPBSCT for first-line treatment showed 3-year OS rates of up to 57% without and up to 55% with consolidating WBRT.49,51-53 Illerhaus et al recently showed the results of a pilot study wherein they intensified the chemotherapy dose and restricted WBRT to patients who did not respond completely to chemotherapy to limit neurotoxicity.54 Between February 2003 and June 2006, 13 patients with median age of 54 years were treated. Patients proceeded to high-dose chemotherapy and autologous stem cell transplantation (autoSCT) irrespective of their response to highdose MTX. The treatment schedule included 3 sequential steps: (1) two to four cycles of high-dose MTX 8 g\m2 at 10-day intervals; (2) two 21-day cycles of Ara-C and thiotepa followed by filgrastim and stem cell mobilization after the first cycle; and (3) conditioning with carmustine and thiotepa followed by autoSCT. Eleven of 13 patients proceeded to high-dose chemotherapy and autoSCT, resulting in 7 CRs and 4 PRs. Three patients were referred for WBRT after high-dose chemotherapy and autoSCT as a result of PR; 1 patient with PR refused WBRT and died. With a median follow-up of 25 months, 10 out of 13 patients (77%) are alive in excellent mental and general condition. A prospective, multicenter phase II trial using this treatment regimen is ongoing. Soussain et al reported the results of a prospective, multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem cell rescue (HCR) in immunocompetent adult patients with PNCSL or intraocular lymphoma after failure of a high-dose MTX–based regimen.55 Between January 2000 and December 2005, 43 patients (median age, 52 years) were enrolled in the study. Five patients were aged > 60 years. All of the patients had received highdose MTX, combined with either lomustine or procarbazine, or with anthracycline, cyclophosphamide, vincristine, and prednisone. The salvage treatment consisted of two 28-day cycles of the high-dose Ara-C and etoposide (CYVE) regimen. This regimen was chosen because of the lack of cross-resistance between Ara-C, etoposide, and MTX and for its efficacy in adults and children with Burkitt lymphoma and initial CNS disease. Peripheral blood stem cells were harvested after the first course of CYVE. Intensive chemotherapy consisted of high-dose thiotepa plus busulfan and cyclophosphamide. With a median follow-up of 36 months among survivors, 16 patients remained alive. In the intent-to-treat analysis, the median OS was 18.3 months. The 2-year probabilities of OS and progression-free

survival were 45% and 43%, respectively. A total of 27 patients received intensive chemotherapy plus HCR. Before intensive chemotherapy plus HCR, 12 patients were in complete remission, 3 were in partial remission, 1 had stable disease (SD), and 11 had PD. When re-evaluated after intensive chemotherapy plus HCR, 26 patients were in complete remission, and 1 had PD. Thirteen patients (47%) relapsed after intensive chemotherapy plus HCR.

Treatment of Patients With Leptomeningeal Lymphoma Meningeal treatment is necessary because meningeal involvement has been demonstrated in almost all patients with PCNSL at autopsy. There are 3 treatment options for meningeal treatment. The first is spinal cord irradiation, which is associated with relevant marrow toxicity27; therefore, as a rule, craniospinal irradiation is recommended only in the case of a positive cytology on CNS examination, and no chemotherapy is given.24 The other options are high-dose systemic chemotherapy or intrathecal drug delivery. The latter option is not routinely used because of the lack of a prospective assessment of its survival effect, the increased risk of severe neurotoxicity, and the impossibility of performing a lumbar puncture in up to one third of patients because of elevated intracranial pressure. At any rate, if patients received high-dose MTX or Ara-C, the role of intrathecal treatment is negligible.

Neurotoxicity Treatment-related neurotoxicity is a significant problem in patients with PCNSL because cognitive dysfunction often limits patients’ ability to return to their premorbid level of social and professional functioning. Elderly patients with PCNSL are especially vulnerable to treatment-related neurotoxicity. Among the different therapeutic strategies for PCNSL, WBRT followed by MTX-based chemotherapy seems to produce the highest incidence of neurotoxicity, followed by WBRT alone and then chemotherapy alone. Because of the increased risk of neurotoxicity in elderly patients, many authorities recommend deferral of WBRT to individuals aged > 60 years with newly diagnosed PCNSL.1 Cognitive outcome, however, has been assessed systematically in a limited number of studies, and each involved a relatively small number of patients. In a recent review by Correa et al, the studies that assessed cognitive outcome after treatment with WBRT and high-dose MTX or with WBRT and BBB-disruption chemotherapy were retrospective and

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PCNSL in Immunocompetent Patients reported cognitive impairment in the majority of the patients. Cognitive domains most likely to be impaired included attention, executive functions, memory, naming, and psychomotor speed.56 The studies that reported cognitive outcome in patients with PCNSL treated with high-dose MTX alone or with BBB-disruption chemotherapy were mostly prospective. Several studies documented cognitive impairment before therapy in the areas of attention, executive functions, memory, psychomotor speed, and language. Posttreatment follow-up reported either stable or improved cognitive performance, but in a subset of patients, there was a decline in attention, memory, psychomotor speed, and word fluency.56 Correa and colleagues’ review indicated that there were methodological problems that limited the comparisons between studies. These problems concerned the absence of a baseline cognitive evaluation, different posttreatment follow-up intervals, the inclusion of patients undergoing treatment or in disease progression/partial remission, and the administration of a different set of tests. A possible strategy for reducing neurotoxicity is treatment with induction chemotherapy followed by reduced-dose WBRT. This approach was applied in a recent prospective study in which neuropsychologic functioning was assessed in 12 patients with newly diagnosed PCNSL. Neuropsychologic evaluations were collected at diagnosis, after induction chemotherapy, and at 6 and 12 months after WBRT. Nine patients completed cognitive evaluations 18 and 24 months after treatment. At diagnosis, patients had impairments in executive functions, verbal memory, and motor speed. After induction chemotherapy, there was a significant improvement in executive functions and verbal memory that remained stable up to 12 months after treatment. Among the patients who completed a 2-year followup, there was a significant improvement in the executive functions and a trend toward a decline in the verbal memory domain.57

Treatment of Patients With Intraocular Lymphoma The primary treatment of intraocular lymphoma remains to be defined, but there is no evidence to suggest that intraocular lymphoma should be treated in a different way from other presentations of PCNSL. Chemotherapy efficacy against intraocular lymphoma is dependent on intraocular drug pharmacokinetics and the limitations in achieving adequate intraocular drug concentrations when administered by the I.V. route. As a consequence, ocular failure is common. Better disease control combining ocular irradiation with MTX-based chemotherapy has been reported. New therapeutic strategies include the administration of high-dose chemotherapy supported by autoPBSCT and the intravitreal injection of MTX, with or without thiotepa.58

Recurrence After CR to initial therapy, PCNSL may recur in other CNS sites, including the spinal cord and the eye, or in another anatomic site such as the meninges, and recurrence is the cause of death of the majority of patients. Thus, strategies designed to prevent recurrence might prolong survival in patients with PCNSL. O’Neill et al treated 5 immunocompetent patients at risk for PCNSL recurrence with high-dose methylprednisolone to prevent “trafficking” of malignant cells into the CNS.59 Methylprednisolone was chosen because of its ability to stabilize the BBB. Three men aged 62, 76, and 78 years, whose survival was projected to be 6.6 months, began treatment

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after achieving CR with initial RT alone and survived 27, 37, and 59 months, respectively, after the end of treatment. No patient died of recurrent disease in the CNS. A 20-year-old man treated with methylprednisolone after successful combined-modality therapy was alive 75 months after diagnosis without evidence of recurrence. Finally, a 34-year-old man underwent unsuccessful salvage therapy after recurrence and then began methylprednisolone. He died of progression of PCNSL. Corticosteroids inhibit the externalization of cell adhesion molecules, which is the putative mechanism of their anti-inflammatory effect. If repopulation of the CNS by malignant cells is the mechanism of recurrence, then corticosteroids could interrupt this cascade. About one half of immunocompetent patients with PCNSL achieving CR with primary treatment experience relapse, whereas 10%-15% present with refractory disease. Prognosis for both recurrent and refractory disease is poor, with most patients dying within 2 to 4 months.60 The role of salvage therapy in PCNSL has not yet been defined; some anecdotal observations have suggested that second-line treatment could achieve a further remission and improve neurologic symptoms. Neuwelt et al re-treated 9 out of 10 patients with recurrent PCNSL: 4 patients were still alive at the time of the report.61 Pollack et al observed a statistically significant improvement in 10 patients receiving second-line therapy compared with 5 untreated patients, and 4 of the former were still alive 6-48 months after recurrence.26 Herrlinger et al treated 7 patients presenting with recurrent PCNSL between 1995 and 1998 using second-line PCV (procarbazine/lomustine/vincristine) chemotherapy because it has shown efficacy as first-line treatment together with WBRT and hydroxyurea and procarbazine and lomustine to penetrate the BBB. Eighty-six percent of the patients had a response to the second-line treatment: 57% achieved a CR, and 28% achieved a PR.62 Some authors, instead, have reported poor results with salvage therapy.20,63,64 Reni et al performed a review of the literature analyzing prognostic factors and the efficacy of salvage therapy from papers reporting results of first-line treatment in 355 cases.65 The study group consisted of 173 patients presenting with treatment failure: the interval between failure and death (TTD) was compared for age at relapse (≤ 60 years vs. > 60 years), type of failure (relapse vs. PD), time to relapse (≤ 12 months vs. > 12 months), and salvage treatment (yes vs. no). Median TTD was similar in younger and older patients, patients with relapsed disease had a longer TTD than patients with PD, early relapse led to a shorter TTD than late relapse, and median TTD was 14 months for patients who underwent salvage therapy and 2 months for untreated patients. A multivariate analysis showed an independent prognostic role for salvage therapy and time to relapse, and salvage therapy not only improved outcome but also the quality of life. In a study of 22 patients with recurrent or refractory PCNSL or intraocular lymphoma, induction with Ara-C and etoposide followed by high-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide produced a CR rate of 72%, with a 3-year survival rate of 64%.66

New Active Drugs and Therapeutic Options Reversible BBB disruption (BBBD) by intra-arterial infusion of hypertonic mannitol followed by intra-arterial chemotherapy

Emanuela Chimienti et al is a strategy that leads to increased drug concentrations in the lymphoma-infiltrated brain and might thus improve survival. First-line treatment with BBBD and high-dose MTX has been associated with acceptable morbidity and high tumor response and survival rates, with only 14% loss of cognitive function at 1 year. In patients with relapsed disease, carboplatin-based chemotherapy plus BBBD produced a 36% response rate, with a median duration of 7 months.58 Prospective and retrospective studies have recently showed some active drugs against PCNSL. Now some of these drugs are being incorporated into ongoing phase II trials assessing new high-dose MTX–based chemotherapy.67 Temozolomide is an oral alkylating agent able to permeate the BBB, is well tolerated, and has additive cytotoxic activity with RT. It has been associated with similar response (31%) and survival (1-year OS, 31%) rates to those reported with other regimens but with an only 2% incidence rate of grade 3/4 adverse events.68 Preliminary data suggest that the combination of temozolomide and rituximab is well tolerated and active.69,70 Rituximab, a chimeric monoclonal antibody (MoAb) directed against the B-cell antigen CD20, can be safely infused at high doses to attain higher CFS concentrations. Promising effects with intraventricular rituximab have been reported in a few cases of leptomeningeal lymphoma; however, administration of I.V. rituximab has shown disappointing results.7,58 Topotecan, a camptothecin derivative that inhibits the enzyme topoisomerase I, produces an objective response in 33% of patients and 1-year OS rate of 39%, with acceptable toxicity.71 In a recent phase II study, 15 patients with relapsed or refractory PCNSL were treated with topotecan for 5 consecutive days during each 21-day cycle. Topotecan was associated with a 20% CR rate and a 20% PR rate as well as acceptable toxicity and no treatment-related deaths.72 Pemetrexed inhibits dihydrofolate reductase, like MTX, but it has a broader spectrum of activity than MTX because it targets other sites of inhibition. Recently, Altman and colleagues reported the results of a phase II trial of 8 patients with recurrent PCNSL treated with pemetrexed.73 All patients had large B-cell lymphoma except for 1 patient, who had low-grade lymphoma. All patients had a radiographic response except for the patient with low-grade lymphoma, who had SD. Moreover, this regimen is easy to administer, with relatively minimal toxicity. Preliminary results with radioimmunoconjugates for the treatment of patients with recurrent or refractory PNCSL are now available. Iwamoto and colleagues treated 6 patients with recurrent or refractory PCNSL with ibritumomab tiuxetan, an antiCD20 MoAb linked to a G-emitting imaging radioisotope. Two patients had a PR, 1 patient had SD, and 3 patients had PD within 1 month.74 The duration of response was brief in both patients, and all patients eventually experienced PD. The median OS was 14.3 weeks. Recently, results of a phase II trial of 10 patients with relapsed PCNSL treated with ibritumomab tiuxetan were published.75 Nine patients actually received the treatment. Four patients responded: 1 patient had a CR lasting 30+ months, and 3 patients had short-lived responses of 4 weeks; 5 patients’ disease progressed. All patients experienced grade 3/4 hematologic toxicity but no acute neurotoxicity. Table 2 summarizes the results of these studies.

Table 2 New Drugs in Primary Central Nervous System Lymphoma Number of OR Patients Rate, %

Treatment Temozolomide68

36

31

Median OS 3.5 Months

Rituximab69

7

7

8 Months

Temozolomide Plus Rituximab70

15

53

14 Months

Topotecan71

27

33

8.4 Months

Topotecan72

15

40

32 Months

Pemetrexed73

8

50

Not available

Ibritumomab Tiuxetan74

6

33

14.3 Weeks

Tiuxetan75

9

44

Not available

Temozolomide Plus

Ibritumomab

Abbreviations: OR = overall response; OS = overall survival

Sequence of Treatment The use of chemotherapy in the treatment of patients with PCNSL has raised some concerns not only regarding the best regimens to be used and the best way to administer the drugs but also the optimal sequence of combined treatment (chemotherapy plus RT). Based on some physiopathologic principles, it seems preferable to administer chemotherapy before RT. The permeability of the BBB allows the initial use of hydrophilic drugs administered in a systemic way, and antitumor agents lose efficacy after the initial response to treatment that brings about a repair in the barrier itself. The antineoplastic mechanism of RT is independent of the state of the BBB, so the initial administration of chemotherapy allows the greatest therapeutic advantage of combined therapy, whereas the inverse sequence would have a more limited effect because the response to RT facilitates restoration of the BBB permeability. Another benefit of the initial use of chemotherapy is the negative effect of RT on the efficacy of antineoplastic drugs. In fact, the endothelial proliferation that accompanies RT would limit the diffusion of the drug at the tumor level; moreover, the drug resistance induced by RT in the tumor cells reduces the efficacy of chemotherapy. Additionally, the incidence of neurotoxicity seems to be greatly influenced by the sequence of treatment.23,60,76 Late leukoencephalopathy is a common complication in patients treated with high-dose MTX plus RT. The exact incidence of this residual neurologic dysfunction in large series of patients with PCNSL is unknown, although it is reported to range from 4% to 36%.33 It has been appreciated for a long time that therapeutic irradiation of the brain carries the risk of neurologic dysfunction, categorized as acute, early-delayed, and late-delayed neurotoxicity. The acute reaction occurs under therapy, resulting from transient edema, which can be efficiently treated with corticosteroids. The early-delayed reaction occurs several weeks to months after therapy and presents itself clinically as prolonged episodes of apathy and somnolence, without evidence of focal neurologic deficits. This reaction can be explained by the presence of disseminated plaques of demyelination and petechial hemorrhages in the white matter; it can be transient, but it is progressive and even lethal in some cases. The late-delayed reaction is usually represented by focal radiation necrosis, which appears 3 months to 10 years after therapy, and it is clinically char-

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PCNSL in Immunocompetent Patients Table 3 International Extranodal Lymphoma Study Group Score Parameters

Prognostic Groups

2-Year OS, %

Age > 60 years ECOG PS > 1 LDH > normal level High CSF protein Deep brain lesions

0-1

80

Parameters

Prognostic Groups

Median OS, Years

2-3

48

Age ≤ 50 years or > 50 years KPS < 70% or q 70%

Age a 50 years

8.5

Age > 50 years and KPS q 70%

3.2

Age > 50 years and KPS < 70%

1.1

4-5

15

Abbreviations: CSF = cerebrospinal fluid; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; OS = overall survival; PS = performance status

acterized as progressive focal neurologic dysfunction; the incidence rate is about 5% after conventional external-beam irradiation at total doses of 55-65 Gy. Systemic administration of high-dose MTX could lead to an acute, transient encephalopathy, developing within a few days after I.V. administration, characterized by confusion, somnolence, and neurologic focal symptoms, with or without seizures. Permanent neurologic dysfunction after high-dose MTX could be severe and might be a consequence of a clear leukoencephalopathy with deep brain atrophy and white matter necrosis. Intrathecal administration of MTX could lead to a disseminated necrotizing leukoencephalopathy, clinically characterized by progressive neurologic dysfunction and a frequent lethal course. High-dose systemic therapy with Ara-C is accompanied by neurotoxicity in about 10% of cases, typically presenting as a cerebellar syndrome with ataxia, dysarthria, and rarely, other symptoms like disorientation, lethargy, and apneic episodes. The risk of neurotoxicity is directly related to age; such patients aged ≥ 60 years at the time of diagnosis and treatment have the greatest risk of developing significant neurotoxicity.23,34,77-79

Prognosis Ferreri et al have identified survival predictors in patients with PCNSL and have designed a prognostic score model useful to distinguish risk groups.80 They have analyzed data from 378 patients treated at 23 cancer centers from 5 different countries and have found that age > 60 years, Eastern Cooperative Oncology Group PS > 1, elevated LDH serum levels, high CSF protein concentrations, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a poorer survival. They have used these 5 variables to design a prognostic score model called International Extranodal Lymphoma Study Group (IELSG; Table 3). Each variable was assigned a value of either 0, if favorable, or 1 if unfavorable; the values were then added together to obtain the final score, which has been tested in 105 assessable patients, for whom complete data of all 5 variables were available. The 2-year OS rates were 80%, 48%, and 15% for patients with 0-1, 2-3, and 4-5 unfavorable features, respectively. The prognostic role of this score has been confirmed by limiting analysis to assessable patients treated with high-dose MTX–based chemotherapy (2-year OS rates of 85%, 57%, and 24%, respectively). Abrey et al have proposed another prognostic score, the Memorial Sloan-Kettering Cancer Center (MSKCC) score (Table 4) by collecting data from 338 consecutive patients with PCNSL seen at MSKCC over the past 2 decades.81 The 2 variables included in this prognostic

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Table 4 Memorial Sloan-Kettering Cancer Center Prognostic Model

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Abbreviations: KPS = Karnofsky performance status; OS = overall survival

model were age and PS. With these 2 variables, 3 prognostic classes were obtained: class 1, patients aged ≤ 50 years; class 2, patients aged > 50 years with a Karnofsky PS of ≥ 70%; and class 3, patients aged > 50 years plus Karnofsky PS < 70%. Patients in class 1 had the best prognosis, with a median survival of 8.5 years; patients in class 2 had a median survival of 3.2 years; and patients in class 3 had the poorest prognosis, with a median survival of only 1.1 years. This prognostic score was also significantly associated with the median FFS for classes 1, 2, and 3, which were 2 years, 1.8 years, and 0.6 years, respectively. The advantage of the MSKCC score is its simplicity and widespread applicability, even if it was obtained from a large single-institution series. Application of the IELSG prognostic score to the MSKCC data set showed a statistically significant prediction of survival; however, a statistically significant difference was observed only between patients with 0 to 1 negative prognostic factor and patients with 2 to 5 negative prognostic factors.81,82 Identification of prognostic factors is necessary to determine patient prognosis and to allow appropriate therapeutic decision making; moreover a prognostic score could be used to facilitate comparisons of multiple phase II trials and to apply these results to the community at large; finally, this model could be used to define the appropriate stratification criteria for proper phase III trial designs.

Conclusion The optimal treatment for patients with PCNSL has not yet been established; combined-modality therapy has improved survival, but relapse is still common, and late neurologic toxicity is a significant complication, especially in older patients, who represent the majority of immunocompetent patients with PCNSL. Moreover, the risk of developing neurotoxicity is greater for patients who undergo RT plus chemotherapy compared with patients who undergo the opposite combined-modality treatment. Therefore, if the combined treatment (chemotherapy plus RT) is highly effective for younger patients, efficacious but less-neurotoxic regimens need to be developed for older patients. Preliminary results suggest that high-dose chemotherapy supported by autoPBSCT is feasible in patients with PCNSL; further studies need to be performed to identify the optimal induction and high-dose chemotherapy regimens and to define the best role of this procedure in patients with PCNSL. Salvage therapy prolongs survival in relapsed and refractory patients with PCNSL, but conclusions regarding the best second-line treatment cannot be made because of the extremely various schedules used in the published series. A wider use of well-defined prognostic factors will facilitate the critical comparison of reported therapeutic results; an established prognostic score may allow the identification of different risk groups of patients

Emanuela Chimienti et al who might perhaps require distinct therapeutic strategies. Finally, we suggest that a combined approach including chemotherapy (MTX alone or MTX plus Ara-C) followed by RT should still be considered the gold standard in the management of patients with PCNSL.

Acknowledgments This manuscript was supported by Azzociazione Italiana per la Ricera sul Cancro and Istituto Superiore di Sanità grants.

Disclosures The authors have no relevant financial relationships to disclose.

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