Primary nervous-system lymphoma

Review

Primary nervous-system lymphoma

Primary nervous-system lymphoma Primary nervous-system lymphoma is a rare type of non-Hodgkin lymphoma, which is confined to the nervous system. This disease is managed quite differently from the usual treatment of either primary brain tumours or systemic non-Hodgkin lymphoma. Although whole-brain radiotherapy results in responses in more than 90% of cases, this treatment is associated with high relapse rates and with delayed neurotoxicity in elderly patients. Firstgeneration chemotherapy regimens used successfully in systemic non-Hodgkin lymphoma (eg cyclophosphamide, adriamycin, vincristine, and prednisone) are ineffective in primary nervoussystem lymphoma, partly because of the blood–brain barrier. Median survival of patients treated with radiotherapy alone or chemotherapy plus radiotherapy is similar, and ranges from 10 to 16 months. The addition of methotrexate-based chemotherapy has improved survival for these patients, extending median survival to more than 30 months. When used alone, methotrexate-based chemotherapy is associated with significantly fewer treatment-associated toxic effects. Leptomeningeal lymphoma and intraocular lymphoma are topics of particular relevance in primary nervous-system lymphoma and are addressed in this review. Lancet Oncol 2001; 2: 354–65

Non-Hodgkin lymphoma (NHL) confined to the craniospinal axis and without evidence of systemic involvement is known as primary central-nervous-system lymphoma (PCNSL). However, in some cases the disease is not confined to the central nervous system, and cranial nerves, nerve roots, and the cauda equina may be involved. Primary nervous-system lymphoma (PNSL) is a more accurate descriptive term for this disease, although the term ‘primary’ must be qualified. Most evidence suggests that the malignant event that gives rise to PNSL occurs in a lymphocyte outside the nervous system. Therefore, in this review, the term ‘primary’ in PNSL indicates that the nervous system is the only site of detectable disease, according to currently available diagnostic modalities. Finally, PNSL should be distinguished from secondary nervous-system lymphoma, which occurs when a patient with a history of systemic NHL experiences dissemination of lymphoma to the nervous system, most commonly the leptomeninges. In 1929, Bailey rekindled interest in rare brain tumours that he described as “intracranial sarcomatous tumors of leptomeningeal origin”.1 Fourteen years later, Kinney and Adams reported a pathological analysis of two brain tumours that matched Bailey’s description of ‘perithelial sarcoma’. Based on the gross and microscopic appearance 354

Courtesy of K Braaten, Massachusetts General Hospital

Scott R Plotkin and Tracy T Batchelor

Figure 1. Gross coronal brain section from a patient with PNSL, showing tan–white appearance of tumours in a periventricular location (arrowed).

of these tumours, Kinney and Adams referred to them as ‘reticulum cell sarcomas’ and suggested that they could be of mesodermal origin within the brain.2 Subsequently, the tumour has been properly identified as a type of NHL involving the nervous system. About 75% of PNSL cases are large B-cell lymphomas, according to the Revised European and American Lymphoma (REAL) classification system; the largest subgroup is diffuse, centroblastic lymphoma, according to the Kiel classification system.3 However, histological subclassification of PNSL by means of existing systems shows no relation to prognosis and has little clinical value. Pathological studies have shown that these tumours typically infiltrate the perivascular spaces and invade adjacent brain parenchyma (Figures 1 and 2). The proliferating edges of the tumours generally consist of a mixture of tumour cells, reactive T lymphocytes, and reactive astrocytes. The site of origin of the malignant lymphocyte that results in PNSL remains unknown. One theory is that the malignant clone arises from a lymphocyte normally trafficking through the nervous system. Others believe that it arises in an extraneural location and either possesses specific tropism for the nervous system or is incompletely eradicated from the nervous system by the host immune system. Support for the extraneural origin of PNSL comes SRP and TTB are at the Neurology Service, Massachusetts General Hospital, Boston, USA. TTB is also at the Brain Tumour Center, Massachusetts General Hospital, Boston, USA. Correspondence: Dr Tracy T Batchelor, MD, Cox 315, Massachusetts General Hospital Cancer Center, 100 Blossom Street, Boston, MA 02114, USA. Tel: +1 617 724 8770. Fax: +1 617 724 8769. Email: [email protected] THE LANCET Oncology Vol 2 June 2001

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Review

Primary nervous-system lymphoma

Courtesy of K Braaten, Massachusetts General Hospital

Epidemiology

Figure 2. (a) Haematoxylin and eosin stain of a brain biopsy specimen from a patient with PNSL showing large, atypical lymphoid cells, many resembling immunoblasts and centroblasts, with clustering around a cerebral blood vessel. (b) An immunohistochemical stain using the L26 antibody reveals that the malignant lymphocytes are B cells (brown staining of cytoplasmic membrane).

from studies of the molecular and immunophenotypic profile of tumour cells derived from immunocompetent patients with PNSL. These studies have shown that many of the cells of PNSL have mutations of the BCL6 protooncogene, and BCL6 protein expression has been found on all cells. Since BCL6 is expressed selectively by B cells in the germinal centre, these findings suggest that PNSL may arise from B cells related to the centre. Because there is no germinal centre structure in the brain, the tumour may arise in an extraneural germinal centre, with subsequent localisation to the nervous system.4 In a study of genes encoding the variable region of immunoglobulin heavy chains (VH genes) from the tumour specimens of five PNSL patients, the high proportions of somatic mutations and intraclonal nucleotide heterogeneity also suggest that the B cell of origin arises in a germinal centre and not in the central nervous system. Thus, just as the term ‘central’ in PCNSL was an inaccurate description of this disease entity, the term ‘primary’ may also be incorrect.3 In addition to research on BCL6 mutations, other genetic studies of PNSL have shown that another common genetic alteration is deletion of the tumour suppressor gene, P16, which occurs in 50% of cases.5 No studies have reported on whether any of these biological markers is related to prognosis. THE LANCET Oncology Vol 2 June 2001

PNSL is a rare tumour, with an incidence of 0.43 per 100 000 person years.6 There are about 1000 cases of PNSL in the USA each year, which account for 4% of all malignant primary brain tumours and 1% of all cases of NHL.6 However, the incidence of PNSL has increased almost three-fold over the past three decades, in parallel with an increase in systemic NHL.7 The increasing incidence has been most striking in the elderly population and can only partly be attributed to the epidemic human immunodeficiency virus (HIV). The only clearly established risk factors for PNSL are immunodeficiency states, including infection with HIV. An increased incidence of PNSL has been observed in organ-transplant recipients treated with immunosuppressant drugs. Other types of cancer, and immune-mediated disorders such as rheumatoid arthritis and idiopathic thrombocytopenic purpura, have also been reported at higher frequency in patients with PNSL.8 No environmental risk factors for PNSL have been identified.

Diagnosis PNSL is associated in many cases with acute to subacute clinical deterioration, generally involving cognitive function. Unlike other types of primary brain tumours, seizures are uncommon, probably reflecting the fact that PNSL mainly affects subcortical structures. The neuroimaging technique of choice is gadolinium-enhanced cranial magnetic resonance imaging (MRI), which typically reveals one or more homogeneously enhancing periventricular brain masses (Figure 3). The best method for diagnosis of PNSL is stereotactic biopsy of an enhancing mass lesion. In rare cases, the diagnosis is established by vitreal aspiration or cytopathology or flow cytometry of cerebrospinal fluid (CSF). Staging and prognosis

At the time of diagnosis, most cases of PNSL consist of solitary (75%) or multiple (25%) masses in the brain parenchyma. However, the leptomeninges may be involved in 25–41% of cases, and the eye in up to 20% of cases.8,9 Ocular involvement may consist of malignant infiltration of the retina, choroid, or vitreal fluid. Therefore, in a patient with newly diagnosed PNSL, the staging evaluation should include a contrast-enhanced brain MRI scan, ophthalmic examination, including slit-lamp assessment, and CSF cytopathology if a lumbar puncture can be done safely. In almost all patients who present with lymphoma in the brain parenchyma, computed tomography of the chest and abdomen, bone scan, gallium scan and a biopsy of the bone marrow do not reveal evidence of disease outside the central nervous system. These diagnostic procedures should only be done if symptoms or signs indicate disease in extraneural sites. Prospective studies of potential prognostic markers in PNSL have consistently indicated that younger age and better performance status are related to longer overall survival.10-12 In a retrospective study of 226 patients with PNSL, CSF protein concentration was also identified as an independent prognostic factor13 in a multivariate analysis. 355

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Review

Primary nervous-system lymphoma

Figure 3. (a) A TI-weighted, gadolinium-enhanced cranial MRI from a patient with PNSL. A characteristic single, homogeneously enhancing mass (arrowed) lies adjacent to the ventricular system, (b) A T2-weighted cranial MRI from the same patient, showing the characteristic isointense to hyperintense appearance of the mass (arrowed).

As mentioned previously, histological subtypes of PNSL are not related to clinical outcomes and therefore have no prognostic value.

Treatments for newly diagnosed PNSL The typical treatment modalities for primary brain tumours (surgical resection and radiotherapy) and for systemic NHL (cyclophosphamide, adriamycin, vincristine, and prednisone – CHOP – chemotherapy) are largely ineffective for PNSL, at least partly because of the diffuse nature of the disease and the existence of the blood–brain barrier (BBB).

corticosteroid nor the optimum effective dose has been determined for PNSL. Since routine treatment of intracranial mass lesions with corticosteroids can lead to regression of PNSL,19–21 stereotactic biopsy may be technically difficult. Moreover, even if residual tumour persists after treatment with corticosteroids, the histology may be so disrupted that definitive pathological diagnosis is impossible. Therefore, when PNSL is suspected, on the basis of the radiographic appearance of a brain mass, corticosteroids should be withheld, if clinically feasible, until after biopsy. Surgery

Corticosteroids

After treatment with corticosteroids, PNSL may regress, as systemic NHL does. Corticosteroids can reduce tumourassociated oedema and cause lysis of malignant lymphocytes. The latter effect is presumably mediated through glucocorticoid receptors14 and may involve apoptosis of malignant lymphocytes.15 Corticosteroids are included in many chemotherapy regimens for systemic NHL and PNSL. Although initial response rates (complete and partial responses) may be as high as 40%, complete radiographic responses after administration of corticosteroid alone are rare.16,17 In those patients who do achieve a complete responses with steroids alone, the duration of response ranges from 6 to 60 months,18 with most patients experiencing early relapse. Neither the specific type of 356

Surgery is an important treatment for many types of primary brain tumours. However, resection of PNSL is technically difficult owing to the multifocal nature of the disease and the typical location, deep within the brain.22 In one series of 83 cases, the mean survival of patients given supportive care alone was 3.3 months, compared with 4.6 months in those who underwent surgical resection.23 In a separate review of 693 cases from 86 reports, the median survival after surgery for PNSL was 1 month.24 Surgical resection alone is therefore not an effective therapy for PNSL. The main role of surgery in such cases is to establish the diagnosis by means of stereotactic biopsy. Resection is reserved for the rare patient who presents with rapid neurological deterioration due to increased intracranial pressure and brain herniation. THE LANCET Oncology Vol 2 June 2001

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Primary nervous-system lymphoma

Radiotherapy

Review

Basal membrane

Radiotherapy is useful in the Normal cell treatment of both malignant gliomas Intercellular cleft Tumour cell and systemic NHL25 and has historically been considered an Astrocyte foot process Fenestration essential modality in the treatment of PNSL. Because of the diffuse nature of Pgp PNSL, radiation must be Tight junctions administered to the whole brain rather than to the tumour alone, so Nucleus focal radiosurgical techniques do not Mitochondria have a role in its treatment. Early Pinocytotic vesicles studies documented a significant Extracerebral Intracerebral Brain tumour increase in median survival in capillary capillary capillary patients treated with whole-brain radiotherapy (WBRT) and surgery, Fenestrations No fenestrations Fenestrations compared with patients treated with Intercellular clefts Tight junctions, no Disrupted tight junctions No tight junctions intercellular clefts Intercellular clefts surgery alone.23 Numerous pinocytotic Very few pinocytotic vesicles Increased pinocytotic vesicles Treatment of PNSL with WBRT vesicles Thick basal membrane No astrocyte foot processes results in responses in more than 90% Numerous mitochondria 26,27 However, the responses of cases. P-glycoprotein expressed are not long-lasting and patients Astrocyte foot processes relapse, in almost all cases in the Figure 4. Diagram of a normal extracerebral capillary, a normal intracerebral capillary with features radiation field. A review of 92 patients of an intact BBB, and an abnormal brain tumour capillary with features of a disrupted BBB. treated with WBRT revealed that 68% experienced recurrent disease; local failure accounted for 93% of the recurrences.26 (no, normal, and disrupted BBB, respectively) are depicted Investigators have suggested that some relapses represent in Figure 4. Tight junctions, thick basal membranes, and reseeding from the CSF rather than true recurrence.27 the absence of fenestrations are all features of a normal However, this idea remains controversial because intracerebral capillary, which will limit penetration of the leptomeningeal involvement occurs in only a minority of BBB. High lipid solubility, chemical neutrality, and low PNSL cases. molecular weight are the usual properties of drugs that will In a prospective, multicentre, phase II trial, WBRT was readily cross an intact barrier (eg the chloroadministered to 41 patients at a dose of 40 Gy with a 20 Gy ethylnitrosoureas). In contrast, the physicochemical propboost to the tumour and a 2 cm margin.28 Complete erties of many drugs used in combination chemotherapy responses were seen in 16 of 29 patients (55%) and partial protocols for NHL limit penetration of the barrier. The responses in another ten patients (35%), giving an overall anthracyclines, cyclophosphamide, and vincristine, drugs response rate of 90%. However, 28 of 41 (68%) patients typically used for the treatment of NHL, are all high relapsed, and median survival was only 11.6 months.28 The molecular weight or polar compounds with poor most common site of relapse was the brain (89%); distant penetration of an intact BBB. Blood vessels within brain recurrence was seen in only 14% of patients. The reason for tumours typically lack some characteristics of a normal failure of local control after an excellent radiographic BBB, resulting in partial barrier disruption within the response to WBRT remains unknown, particularly since tumour. In PNSL, ultrastructural examination of capillaries treatment of systemic NHL produces local control in about reveals thinning of endothelial cells and fenestrations.22 80–90% of cases.25 Treatment-related toxic effects of WBRT These findings suggest that chemotherapeutic agents that were mild, with only three of 41 patients experiencing normally do not penetrate the BBB may have access to grade 3 or 4 toxicity.28 However, long-term neurotoxicity tumour cells in such cases. However, successful treatment may not have been observed because median survival was of a brain tumour and the administration of corticosteroids short. may result in partial or complete reconstitution of the BBB. Data from PET imaging of two patients with PNSL treated with MACOP-B (methotrexate, adriamycin, cyclophosChemotherapy phamide, vincristine, prednisolone, bleomycin) show that Blood–brain barrier In addition to the mechanisms of drug resistance common the BBB is reconstituted after four cycles of to all forms of cancer, there is an additional obstacle in the chemotherapy.29 The researchers suggest that reconstitution treatment of brain tumours – the BBB. This physical of the BBB may prevent the high-molecular-weight, structure, at the level of brain capillaries, separates the hydrophilic drugs in the MACOP-B regimen from reaching cerebral circulation from the systemic circulation and the tumour and contributes to eventual treatment failure. effectively prevents many exogenous molecules from This observation supports the contention that the BBB reaching the central nervous system. The specific features represents an important factor in the resistance of PNSL to of extracerebral, intracerebral, and intratumoral capillaries chemotherapy. THE LANCET Oncology Vol 2 June 2001

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Review

Primary nervous-system lymphoma

Table 1. Non-methotrexate-based chemotherapy plus radiation therapy Chemotherapy (iv and po)

Intrathecal chemotherapy

N

RT dose

Response to chemotherapy

Group 1: CHOP + WBRT

None

10

45 + 10 Gy (50.4 Gy in multifocal disease)

NA

Median progressionfree survival (months) NA

Group 2: WBRT alone Pre-RT CHOP (4 cycles)

None

6

WBRT (4/6): 45 Gy + 10.8 Gy boost

Median overall survival (months)

Reference

Group 1: 25+

60

Group 2: 18

61

CR: 1/6 (16%) PR: 1/6 (16%) PD: 4/6 (67%)

NA

8.5

61

Craniospinal (3/6): 30 Gy Pre-RT: CHOP (2 cycles)

None

53

WBRT at 50.4 Gy

CR: 7/46 (15%) PR: 20/46 (43%) NR: 19/46 (41%)

7.2

10.5

44, 62

Pre-RT CHOD (range 2–3 cycles)

For positive CSF: MTX 12 mg
9 doses

52

WBRT: 41.4 + 18 Gy boost

CR: 10/52 (19%) PR: 25/52 (48%) SD: 3/52 (6%) NR: 8/52 (15%) NA: 6/52 (12%)

9.2

16.1

45

During RT: Hydroxyurea 300 mg/m2

None

16

WBRT: 55–62 Gy

*CR: 12/16 (75%) PR: 4/16 (25%)

NA

41

For positive CSF: MTX 12.5 mg, Ara-C 30 mg, HC 25 mg weekly X 6 weeks

15

WBRT:40 Gy

NA

Post-RT (2 cycles): Ara-C 3 g/m2
4 doses

Post-RT: PCV (indefinite) Group 1: RT only Group 2: Post-RT CHOP

Boost: 14 Gy to tumour + 2 cm margin

Group 1: 22

Group 1: 26

Group 2: 10

Group 2: 14

*Response after RT plus chemotherapy. CHOP/D, cyclophosphamide 750 mg/m2, adriamycin 50 mg/m2, vincristine 1.2–1.4 mg/m2, prednisolone/prednisolone 100 mg/day, dexamethasone 6 mg/m2; Ara-C, cytarabine; RT, radiotherapy; WBRT, whole-brain radiotherapy; iv, intravenous; po, per oral; CR, complete response; PR, partial response; PD, progressive disease; NR, no response; NA, not analysed; CSF, cerebrospinal fluid; MTX, methotrexate

Active areas of investigation in neuro-oncology include the development of administration strategies designed to circumvent the blood–brain barrier and deliver higher concentrations of chemotherapeutic agents to brain tumours, and the selection of drugs with physicochemical properties predictive of blood–brain barrier permeability. Radiation plus chemotherapy

The initial treatment approaches for PNSL were based on the treatments used for systemic NHL, such as CHOP.30 The success of this regimen in systemic NHL suggested that it would be effective in treating PNSL. Four trials of CHOP-based chemotherapy and WBRT are summarised in Table 1. Although initial radiographic response rates of up to 67% have been reported, local recurrence is common and patients die of progressive disease. Median survival is not significantly greater than with WBRT alone. In summary, CHOP shows little efficacy in the treatment of PNSL. Methotrexate is an antimetabolite that can penetrate the BBB when given in high doses by the intravenous route.16,31,32 The first successful use of methotrexate in the 358

treatment of PNSL was reported in 1980, when a 51-yearold patient with recurrent disease survived for more than 12 months after treatment with this drug.33 Subsequently, several studies of methotrexate or methotrexate-based chemotherapy in combination with WBRT were carried out (Table 2). These studies show that the addition of methotrexate alone or methotrexate-based chemotherapy to WBRT results in extension of progression-free survival compared with historical series treated with WBRT alone. Moreover, these studies also show that methotrexate-based chemotherapy administered before radiation results in a high proportion of radiographic responses. However, the addition of chemotherapy in these studies did result in a higher proportion of patients experiencing toxic effects, especially myelotoxicity.

Combined-modality therapy A combined-modality protocol consisting of intravenous methotrexate at 1 g/m2 and intrathecal methotrexate, followed by 40 Gy of WBRT with a 14.4 Gy boost and postirradiation cytarabine (Ara-C) was studied in 31 patients with newly diagnosed PNSL.34,35 No patient THE LANCET Oncology Vol 2 June 2001

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Review

Primary nervous-system lymphoma

achieved a complete response, but 14 of 22 (64%) achieved a partial response to chemotherapy, with a median time to progression of 40.3 months and median survival of 42 months. Treatment-related toxic effects were mild and

included transient renal insufficiency in one patient and clinically significant myelosuppresion in three patients. Late neurotoxicity was seen in ten of 27 patients (37%), typically in those older than 60 years. A subsequent

Table 2. Methotrexate-based chemotherapy with radiation therapy Chemotherapy (iv and po)

Intrathecal chemotherapy

RT dose

N

Response to chemotherapy

Methotrexate 3.5 g/m2

None

11/13 patients: WBRT 30–44 Gy

13

CR: 8/13 (61%) PR: 4/13 (31%) NR: 1/13 (8%)

NA

9+

63

Methotrexate 3.5 g/m2

None

30 Gy + variable boost

25

CR: 14/25 (56%) PR: 8/25 (32%) NR: 3/25 (12%)

32

33

64

Methotrexate 1 g/m2
2

If CSF positive, Ara-C 60 mg every 2 weeks
3

Brain: 45–54 Gy

46

CR: 32/39 (82%)* PR: 5/39 (12%) SD: 1/39 (3%) NR: 1/39 (3%)

NA

33

54

Pre-RT: methotrexate 3.5 g/m2 plus CHOD

None

WBRT: 30 Gy+ variable boost

18

CR: 11/18 (61%) PR: 3/18 (17%) PD: 4/19 (22%)

19.5

25.5

65

Pre-RT MACOP-B (methotrexate 400 mg/m2)

Positive CSF: Ara-C 60 mg, MTX 10–12 mg every week until CSF clear

WBRT: 30–40 Gy, spine: 30 Gy, boost: 55 Gy to primary site

10

CR: 9/10 (90%) PR: 1/10 (10%)

NA

14

49

M-BACOD (methotrexate 3 g/m2)

None

WBRT: 42 Gy (9/14 patients)

14

CR: 10/14 PR: 3/14 NR: 1/14

NA

NA

66

Pre-RT MACOP-B (n = 13)

For positive CSF: Ara-C 50 mg, MTX 12.5 mg, hydrocortisone 12.5 mg BIW

WBRT: median 40 Gy (range 30–45), boost (20/27): 15 Gy

31

CR: 9/27 (33%) PR: 15/27 (56%) NR: 3/27 (11%)

NA

23

50

Craniospinal (9/27): 30–35 Gy, boost (1/9): 10 Gy

18

Group 1: 40.3

Group 1: 42

Group 2: 10 months

Group 2: 21.7

Spine: 36 Gy

or Pre-RT MACOP (n = 18) (methotrexate 2 g/m2) Group 1: Pre-RT chemotherapy: MTX 1 g/m2
2 doses, dexamethasone 16 mg/day Post-RT chemotherapy: Ara-C 3 g/m2
4 doses

Group 1: MTX 12 mg
6 doses

Group 1: WBRT: 40 GY +14.4 Gy boost

31

Group 1: CR: 0/22 (0) PR: 0/22 (0) MR: 3/22 (14%) SD: 5/22 (23%)

Group 2: None

Group 2: None

Group 2: 40 Gy

16

Group 2: CR 16/16

Pre-RT chemotherapy: MTX 2.5 g/m2
5 doses, vincristine, procarbazine Post-RT chemotherapy Ara-C 3 g/m2

None

WBRT: 45 Gy

98

CR: 29/51(57%) PR: 19/51 (37%)

Group 1: MACOP-B with RT

None

Median progressionfree survival

Median overall Reference survival

Not achieved

34, 35

67

30

Group 2: RT only

WBRT: 40 Gy+14 Gy (methotrexate 3.5 g/m2) patients)

20

Group 1: CR: 14/20 (70%) boost (24/28 PD: 3/20 (15%)

Group 1: 24

8

Group 2: CR: 6/8 (75%)† PD: 2/8 (25%)

Group 2: 13

Group 1: 32 PR: 3/20 (15%)

68

Group 2: 18

*Response to chemotherapy plus RT.†Response to RT only. Also see Table 1 legend. MR, minor response Chemotherapy regimens: M-BACOD: Methotrexate 3–3.5 mg g/m2, Cyclophosphamide 600 mg/m2, bleomycin 4 mg/m2, doxorubicin 45 mg/m2, vincristine 1 mg/m2, dexamethasone 30 mg/m2 MACOP: Cyclophosphamide 350 mg/m2, doxorubicin 50 mg/m2, methotrexate 2 g/m2, vincristine 1.4 mg/m2, prednisolone 60 mg/day MACOP-B: Cyclophosphamide 250 mg/m2, adriamycin 50 mg/m2, cincristine 1.4 mg/m2, prednisolone, and MTX 400 mg/m2 or bleomycin 10 mg/m2 CHOP/D: Cyclophosphamide 750 mg/m2, adriamycin 50 mg/m2, vincristine 1.2–1.4 mg/m2, prednisolone/prednisolone 100 mg/day, dexamethasone 6–10 mg/m2

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Review variation of this protocol increased the dose of methotrexate and added a lipophilic agent, procarbazine.36 In a study of this regimen, 52 patients received five cycles of intravenous and methotrexate (3.5 g/m2) intrathecal methotrexate, intravenous vincristine, and oral procarbazine, followed by 45 Gy of WBRT and intravenous cytarabine (3 g/m2) after radiation. The overall response rate to induction chemotherapy was 90% (56% complete and 33% partial response). The median survival was 60 months for all patients. Grade 3 or 4 haematological toxic effects occurred in 31 of 52 (60%) patients.36 Delayed neurotoxicity

Primary nervous-system lymphoma

Figure 5. A cranial MRI FLAIR sequence in a patient with delayed neurotoxicity after methotrexate and whole brain radiation therapy. There is a mild ventricular enlargement and diffuse hyperintense signal abnormality in the bilateral hemispheres, mainly in the subcortical regions.

An important complication of combined-modality therapy is delayed neurotoxicity. The effects are characterised by a combination of memory impairment, gait failure, and incontinence. Radiationinduced leucoencephalopathy is a well-documented consequence of WBRT and is characterised by diffuse signal abnormality in the white matter of both cerebral hemispheres, cortical atrophy, and ventriculomegaly seen in cranial MRI studies (Figure 5). Concurrent WBRT and methotrexate chemotherapy is associated with an increased frequency of leucoencephalopathy, especially when methotrexate is administered after radiation. For this reason, the delivery of WBRT is delayed until the completion of methotrexate chemotherapy in many protocols. In one study of 117 patients treated with combined-modality therapy (radiation plus chemotherapy), 37 (32%) developed late neurotoxic effects. Median time to onset of symptoms was 9 months, and the symptoms were associated with a decline in median Karnofsky performance score from 80 to 50. Significant risk factors for neurotoxicity included age greater than 60 and a history of WBRT.37 Because of the neurotoxicity associated with WBRT in people over the age of 60, the use of this treatment modality in these patients may be questioned. In a prospective study that included 34 patients older than 60 years, there was no difference in survival between those who received WBRT as part of the treatment regimen and those who did not receive WBRT. However, the causes of death in the two groups differed. There was delayed neurotoxicity in 83% of patients who received WBRT. These patients were likely to die of complications caused by delayed neurotoxicity, whereas those who did not receive WBRT were more likely to die of disease recurrence.36 The usefulness and safety of WBRT in elderly patients with PNSL is therefore questionable.

approaches generally involve the use of chemotherapeutic drugs with proven antilymphoma activity and physicochemical properties compatible with penetration of the BBB. Seven studies of chemotherapy alone are summarised in Table 3. Blood–brain-barrier disruption

One way of improving drug delivery into the brain is to disrupt the BBB, and then to administer intra-arterial or intravenous chemotherapy. Osmotic agents are delivered into an artery and cause transient disruption of the barrier, so that drugs infused into the circulation can reach the brain parenchyma and the brain tumour. In a review of 74 patients with PNSL treated in this way over 15 years, 48 patients (65%) achieved complete responses, 14 patients (19%) had partial responses, and 12 patients (16%) had stable or progressive disease.38 For patients who achieved complete responses, disease-free survival was 48% at 2 years. The estimated 5-year survival rate was 42% and the estimated median survival was 40.7 months. However, disruption of the BBB was associated with significant procedure-related, acute toxic effects. Of 74 patients, four died within 30 days of a procedure, five had a stroke, and one experienced status epilepticus.In contrast to the high proportion of acute toxic effects, there was little late neurotoxicity in this cohort of patients treated without WBRT. Comprehensive neuropsychological testing was performed in 31 patients who achieved a complete response lasting longer than one year. In this cohort of patients there were no cases of dementia and significant improvements were noted in several cognitive domains.38 Although this study revealed the efficacy and lack of delayed neurotoxicity of chemotherapy alone in patients with PNSL, the technical complexities of disruption of the BBB and the associated acute toxic effects limit wide application of this method in the treatment of PNSL.

Chemotherapy alone

The recognition that neurotoxicity occurs in a significant proportion of PNSL patients who receive WBRT has led to efforts to defer or eliminate WBRT in this group. These 360

Methotrexate

Over 10 years ago, several groups of investigators began to give patients with newly diagnosed PNSL methotrexate THE LANCET Oncology Vol 2 June 2001

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Primary nervous-system lymphoma

Table 3. Methotrexate-based chemotherapy alone Chemotherapy (iv and po)

Intrathecal chemotherapy

N

Response to chemotherapy

Median progressionfree survival (months)

Median overall survival (months)

BBBD: Cyclophosphamide 15 mg/kg or 500 mg/m2, etoposide 150 mg/m2
2 days (ia), MTX 2.5 g
2 days, procarbazine 1000 mg/d
14 days 30 patients)

None

74

CR: 48/74 (65%) PR: 14/74 (19%) SD or PD: 12/74 (16%)

NA

40.7

38

MTX 3.5 g/m2 alone (n = 4) or with CHOD (n = 4)

None

8

CR: 8/8 (100%)

32+

36+

40

Induction: MTX 8 mg/m2 Maintenance: MTX 3.5 g/m2

None

11

CR: 9/11 (82%) PR: 1/11 (9%) PD: 1/11 (9%)

Not reached at time of publication

Not reached at time of publication

MTX 8 g/m2
3 cycles or until response, then 3.5 g/m2
3 monthly cycles, then indefinitely every 3 months

None

31

CR: 20/31 (65%) PR: 11/31 (35%)

16.7

30.4

39

MTX 8 g/m2 for induction (up to 8 cycles), consolidation (2 cycles) and maintenance (11 monthly cycles)

None

25

CR: 12/23 (52%) PR: 5/23 (22%)

Not reached at 1 year

Not reached at 1 year

41

Induction: MTX 8 g/m2 Maintenance: MTX 3.5 g/m

None

10

CR: 6/10 (60%) PR: 3/10 (30%) NR: 1/10 (10%)

18

36

42

13

CR: 10/13 (77%) PR: 2/13 (15%) NR: 1/13 (8%)

NA

30.5

43

14

CR: 11/14 (79%) PR: 3/14 (21%)

16.5

Not reached at 3.3 years

54

MTX 1–3.5 g/m2
4–5, MTX 12 mg
vincristine 1.4 mg/m2
5, 5–6 doses procarbazine 100 mg/m2
3 (Ara-C 3 g/m2 in 4 patients, thiotepa 40 mg/m2
3 and corticosteroids in 5 patients) MTX 8.4 g/m2, thiotepa 35 mg/m2, vincristine 1.4 mg/m2, dexamethasone 16–24 mg/day

Ara-C 50 mg
3 MTX 12 mg
2 (5 patients)

Reference

MTX, methotrexate; Ara-C, cytarabine; iv, intravenous; po, oral; BBBD, blood–brain-barrier disruption; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NR, no response; NA, not analysed

alone and deferred WBRT.39,40 In one study, 31 patients were treated with methotrexate alone.39 Induction methotrexate was administered at 8 g/m2, followed by indefinite maintenance therapy at 3.5 g/m2 every 3 months. A median of ten cycles per patient (range 3–30) was given. The overall response rate was 100%, with 20 complete responses (65%) and 11 partial responses (35%). The median progression-free survival was 16.7 months, and the median overall survival was 30.4 months. After 375 cycles of methotrexate, toxic effects were minimal; leucopenia without fever was documented in only four cycles and reversible renal insufficiency was seen in only three cases.39 On the basis of these promising results from a single institution, 25 patients were treated with high-dose methotrexate monotherapy in a phase II cooperative group trial. Patients on this protocol received methotrexate (8 g/m2) every 2 weeks until complete response (induction), then every 2 weeks for a month (consolidation), and then every 4 weeks for 11 months (maintenance). The overall response rate was 74% (52% complete responses and 22% partial responses) and median progression-free and overall survival were both more than 14 months at last follow-up. After 270 cycles of THE LANCET Oncology Vol 2 June 2001

methotrexate, toxic effects were minimal (two episodes of grade 4 and 14 episodes of grade 3).41 Elderly patients

Since elderly patients are more susceptible to radiationinduced neurotoxic effects, studies of chemotherapy alone are important in this group. In one study of methotrexate monotherapy for PNSL, ten elderly patients (median age 72.5 years) were treated with intravenous methotrexate, 8 g/m2 for induction, and then 3.5 g/m2 for maintenance therapy.42 Six patients achieved complete responses and three achieved partial responses. Toxic effects were mild and did not interfere with treatment. The median time to progression was 18 months and the median survival was 36 months. In another study, 13 patients over the age of 50 were treated with chemotherapy alone.43 All patients received intravenous methotrexate (1.0 or 3.5 g/m2), oral procarbazine, intravenous vincristine, and intrathecal methotrexate; five received additional intravenous thiotepa and four received additional intravenous cytarabine. Ten patients achieved complete responses and two achieved partial responses; the overall response rate was 92%, and median survival was 30.5 months. The results of these two 361

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Review

Primary nervous-system lymphoma

studies are notable because older age is a poor prognostic factor in PNSL patients treated with WBRT, with or without chemotherapy.28,44–46

Treatment for refractory and relapsed PNSL Although many treatments for PNSL yield good initial response rates, almost all patients relapse. Treatment for relapsed or refractory PNSL has not been extensively studied, and no standard recommendations exist. A retrospective analysis of 173 patients from 24 studies who experienced recurrent or progressive disease showed that patients who received salvage chemotherapy had longer survival (14 months) than those who were untreated (2 months).47 Unfortunately, performance data for these patients were not available at the time of relapse or progression. As the researchers pointed out, these data could potentially confound the results, because patients with poor Karnofsky performance score, a factor associated with poor outcome, are less likely to receive salvage chemotherapy. Because 26 different regimens were used in 55 cases, no conclusions can be drawn about specific chemotherapy regimens.47 A summary of specific chemotherapy regimens for refractory or relapsed PNSL is given in Table 4. Most of these studies have been small, uncontrolled case series and definitive conclusions cannot be drawn from these data. From observations up to this point, several drugs or combinations of drugs seem to have some efficacy in these patients and deserve further study. Whole-brain radiotherapy

In patients who were initially treated with chemotherapy alone, WBRT remains an option at the time of relapse. In a study of 16 patients who relapsed after achieving complete responses with high-dose methotrexate, WBRT was

administered at a median dose of 40 Gy. Complete responses occurred in 38% of patients and partial responses in 38% of patients; mean survival was 6.8 months after WBRT.48 Univariate analysis of patients treated with multiple regimens suggests that the addition of WBRT to chemotherapy may lengthen time to death after recurrence or progression.47 Methotrexate

In a series of patients treated with high-dose methotrexate alone,39 nine were identified who initially achieved complete responses, but subsequently relapsed. These patients were then treated again with high-dose methotrexate. Complete responses were seen in six patients (67%) and partial responses in three (33%). The median progression-free survival was 9.7 months for all nine patients, and 22.9 months in the six patients with complete responses.39 Development and implementation of phase I and phase II studies for relapsed or refractory PNSL should receive high priority in cooperative groups. In addition to the identification of new agents for this group of patients, these studies may identify drugs that can be combined with existing chemotherapy regimens for newly diagnosed PNSL.

Special topics Leptomeningeal lymphoma

Many protocols include intrathecal chemotherapy for patients with malignant cells in the CSF45,49–51 or for all patients.34,35,43,46,52,53 However, the ability of intravenous methotrexate, when administered in high doses, to penetrate the BBB and reach therapeutic concentrations within the CSF54 may allow deferral or elimination of intrathecal chemotherapy. To date, there has been no direct

Table 4. Treatment for recurrent/progressive PNSL Chemotherapy

N

Response to salvage therapy

Median overall survival (months)

Median survival after salvage chemotherapy (months)

Reference

PCV (range, 1–9 cycles)

7

CR: 4/7

16+

12+

69

PR: 2/7 PD: 1/7 Topotecan 1.5 mg/m2/day
5 days

9

CR: 4/9 PR: 2/9 SD: 2/9 PD: 1/9

NA

10+ in complete responders

70

Carboplatin (ia; n = 2) plus etoposide (iv; n = 10) plus cyclophosphamide (iv; n = 12)

24

CR: 5/17 PR: 2/17 SD: 7/17 PD: 3/17 NA: 7/24

NA

6.7

71

Rituximab (monoclonal antibody to CD-20) 375–500 mg/m2 weekly
4

3

PR: 1/3 (33%) SD: 2/3 (66%)

Not calculated

Not calculated

72

Thiotepa 750 mg/m2, misulban 10 mg/kg, cyclophosphamide 120 mg/kg, +/ Ara-C and etoposide

10

CR: 6/10 (60%) PR: 4/10 (40%)

NA

Not reached after 24 months

73

Also see Table 1 legend. Chemotherapy regimens: PCV: procarbazine 60 mg/m2 (day 8 to 21), CCNU 100 mg/m2 (day 1), vincristine 2 mg (day 8 and 29). CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; iv, intravenous; ia, intra-arterial

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Primary nervous-system lymphoma

comparison between regimens with and without intrathecal chemotherapy. The most commonly used intrathecal agents are cytarabine and methotrexate. Traditionally, cytarabine is given twice a week, because of the short half-life of the drug within the CSF (3.4 hours). This schedule requires surgical insertion of a ventricular reservoir in many patients and may have a negative impact on quality of life. Moreover, the pharmacokinetic profile of cytarabine in the CSF does not lead to sustained exposure of malignant lymphocytes to the drug at cytotoxic concentrations. A sustained-release form of liposomal cytarabine has been developed for the treatment of neoplastic meningitis and can be administered every 2 weeks, because it has a longer half-life in CSF (141 hours). In a randomised study of intrathecal cytarabine versus liposomal cytarabine in lymphomatous meningitis, the liposomal form of the drug was associated with a significantly higher cytological response rate (71% versus 15%) and a non-significant increase in time to progression and survival. Patients treated with liposomal cytarabine also experienced greater improvement in mean Karnofsky performance score and survival adjusted for quality of life.55 On the basis of the evidence that high-dose methotrexate can penetrate the BBB and achieve micromolar concentrations in the CSF, our current practice is to defer chemotherapy in the initial treatment of PNSL patients with or without leptomeningeal dissemination. In patients who have persistent leptomeningeal lymphoma after four cycles of high-dose methotrexate (8 g/m2), intrathecal liposomal cytarabine is recommended. Intraocular lymphoma

Intraocular lymphoma (IOL) consists of lymphomatous involvement of the vitreous and aqueous humour, retina, and choroid, and may occur alone or as a complication of PNSL. Blurred vision, diminished visual acuity, and floaters are the most common symptoms of this disease. Bilateral involvement occurs in more than 80% of patients. The slitlamp examination is abnormal in more than 90% of cases, revealing uveitis, vitreitis, and retinal or choroidal infiltrates. About 80% of patients with an initial diagnosis of IOL develop PNSL, and up to 20% of patients with PNSL develop IOL during the course of the disease.8 Standard care for IOL consists of orbital radiation and local control is achieved in most cases. However, if no additional treatment is administered, about 90% of these patients relapse or develop PNSL.56 Moreover, orbital radiation is associated with substantial adverse effects, including cataract formation, retinal detachment, and optic-nerve atrophy.57 The use of intravitreal methotrexate has been effective in a small number of patients without serious side-effects.58 However, like orbital radiation, it is a focal therapy and will not treat concurrent brain lymphoma. The success of intravitreal methotrexate in the local control of IOL suggests that doses of intravenous methotrexate that are high enough to achieve cytotoxic concentrations of the drug in the eye may be beneficial. In a study of high-dose intravenous methotrexate (8 g/m2) for newly diagnosed cases of PNSL, five patients who also had THE LANCET Oncology Vol 2 June 2001

IOL were treated; four showed complete responses in the brain and uveitis was also resolved in four.41 Other studies have demonstrated that micromolar (presumably cytotoxic) concentrations of methotrexate can be achieved in the aqueous and vitreous humour, after intravenous infusion of methotrexate at a dose of 8 g/m2.59 In some cases, IOL can persist after two or three cycles of high-dose methotrexate, despite the presence of presumably cytotoxic concentrations in the vitreous and aqueous humour. Persistence may be associated with increased cellularity on slit-lamp examination and lower intravitreal methotrexate concentrations. Together, these data suggest that high-dose intravenous methotrexate may be an effective initial treatment for IOL associated with PNSL, but more follow-up data are necessary before definitive recommendations can be made. In patients with IOL and stable visual symptoms and signs, our current recommendation is to treat initially with intravenous methotrexate at 8 g/m2 for four cycles, for as long as vision is maintained and clinical examination remains stable. In patients with persistent disease, according to clinical examination or vitreal aspiration, after four cycles orbital radiotherapy is recommended.

Conclusions Several fundamental issues remain unresolved in the management of PNSL. The need for WBRT in the management of this disease is controversial, especially in elderly patients, owing to delayed neurotoxicity. Patients who receive methotrexate-based chemotherapy alone are at a lower risk of this complication. Current research efforts are focused on the development of radiation-sparing chemotherapy regimens and potentially less toxic WBRT schedules. However, the optimum chemotherapy regimen for maximum response rates and survival and minimum toxicity has yet to be defined. Since large randomised clinical trials are not feasible for this rare disease, alternative study designs are necessary to assess these critical issues in the management of PNSL. There is a clear need for parallel, prospective, multicentre, phase II studies to assess new treatment combinations, the role of intrathecal chemotherapy, optimum management of IOL, and salvage treatment regimens for refractory and relapsed PNSL. So that results from such non-randomised studies can be interpreted, historical databases need to be established for comparison. Advances in the management of PNSL have resulted in improved survival and reduced neurotoxicity for these patients over the past decade. However, survival remains inferior to that reported for

Search strategy and selection criteria Studies published in English were identified from standard electronic databases, PubMed and CancerLit, from 1966 to 2000, through keyword searches including ‘primary central-nervous-system lymphoma’, ‘brain lymphoma’, and ‘central-nervous-system non-Hodgkin lymphoma’. Bibliographies of these studies were used to identify additional relevant publications.

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Review most other forms of NHL. Further improvements in outcome will require the identification of active treatments that are not impeded by the BBB and are not associated with significant neurotoxicity. Acknowledgments

We acknowledge the support provided by the Richard and Nancy Simches Endowed Fund for Brain Tumor Research at the Massachusetts General Hospital. References

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Further information and references, regarding HIV-associated PNSL, appears on The Lancet Oncology's website: http://oncology.thelancet.com

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