Japanese Journal of Clinical Oncology Advance Access published online on April 15, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn027
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author (2008). Published by Oxford University Press. All rights reserved
Results of Treatment of 112 Cases of Primary CNS Lymphoma
1 Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata
2 Department of Neurosurgery, Itoigawa General Hospital, Itoigawa, Niigata
3 Department of Neurosurgery, Niigata Prefectural Central Hospital, Takada, Niigata
4 Department of Neurosurgery, Toyama Prefectural Central Hospital, Toyama
5 Department of Neuropathology, Brain Research Institute, Niigata University, Niigata
6 Biostatistics Center, Kurume University School of Medicine, Kurume
7 Research Center of Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Fukuoka, Japan
For reprints and all correspondence: Ryuya Yamanaka, Research Center of Innovative Cancer Therapy, Kurume University School of Medicine, Asahimachi 67, Kurume, Fukuoka 830-0011, Japan. E-mail: ryaman{at}med.kurume-u.ac.jp
Received January 28, 2008; accepted March 6, 2008
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Background: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found.
Methods: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy.
Results: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4 ± 4.8% [95% confidence intervals (CI)] and 30.2 ± 4.8% (95% CI), respectively. The ProMACE-MOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20–30 Gy WB, and 500 mg/m2 of MTX dose appeared important determinants of OS.
Conclusions: A modest dose of MTX (500 mg/m2) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.
Key Words: methotrexate • neurotoxicity • primary CNS lymphoma • Pro-MACE-MOPP • radiotherapy
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Primary central nervous system lymphoma (PCNSL) is an extranodal form of non-Hodgkin lymphoma occurring in the craniospinal axis. The majority of PCNSLs are high-grade B-cell type non-Hodgkin's lymphomas (1). Tumor manifestation is often diffuse and multifocal and most frequently affects the supratentorial brain parenchyma. PCNSL affects all age groups, with the peak incidence being in the fifth to seventh decades in non-acquired immunodeficiency syndrome patients. An optimal treatment for PCNSL has not yet been established. Several Phase II studies combining chemotherapy with radiotherapy have been carried out in the last decade. Chemotherapy appears to result in a median survival time of 40–60 months (2–13), suggesting that chemotherapy in combination with cranial irradiation at the time of the initial treatment benefits patients in terms of median and disease-free survival. However, identifying the best regimens remains under discussion. The most common approach has been to use drugs that cross the blood–brain barrier and have activity in non-Hodgkin's lymphoma (5,9). As better survival is being achieved for patients with PCNSL, issues related to quality of life, mental function, and performance status of surviving patients have gained importance. Neurotoxicity is typically associated with significant cognitive, psychomotor, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence, and it has a negative impact on quality of life (14,15). Imaging findings have revealed diffuse white matter disease and cortical–subcortical atrophy (16). The core pathophysiological mechanism is the interruption of frontal–subcortical circuits, mediated by radiation damage, possibly caused by microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress (16).
A substantial proportion of the patient data for those who underwent the ProMACE-MOPP regimen was published in 2005 (12). Here more information related to the extended follow-up is presented. The current analysis was conducted retrospectively to examine the long-term results from four different approaches to treatment adopted sequentially between 1982 and 2006, and to describe progression-free survival (PFS), overall survival (OS), and late neurotoxicity for each cohort of patients.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Patients
We identified 112 patients who fulfilled the criteria for the study: negative human immunodeficiency virus status, diagnosis between 1 February 1982 and 31 March 2006, and no other cause for immunosuppression. Three patients were treated at Itoigawa General Hospital and Niigata Prefectural Central Hospital, respectively, 2 were treated at Toyama Prefectural Central Hospital, and the remaining 104 were treated at Niigata University Hospital. Patients were excluded if CNS involvement was part of a systemic lymphoma. All patients gave informed consent as per the ethics committee guidelines of Niigata University Hospital.
Pathology
Until 1994, diagnoses were made using the Working Formulation, and thereafter, were assigned according to the Revised European–American Classification and the World Health Organization classification systems (17–19). There was also a central pathologic diagnosis confirmation by a neurophathologist at Brain Research Institute, Niigata University.
Treatment Intent
The irradiation field included the base of the skull, the exits of the cranial nerves, the optic nerve, and the posterior globe. If ocular involvement was present, then the entire eye was included. Up to 31 August 1987, 29 patients who presented with PCNSL were treated with whole-brain irradiation (WBI) alone. The field was as described above, but the radiation dose was increased to 40 Gy in 20 fractions, with an optional 20 Gy boost to a reduced volume.
From 1 September 1987 until 1 July 1995, we mainly used the MVP protocol (vincristine 1.0 mg/m2, prednisone 40 mg/m2) in association with methotrexate (MTX) (50 mg/m2), delivered intravenously on day 1 for 4 weeks in 26 patients. After three cycles of chemotherapy, WBI at a total dose of 40–50 Gy with conventional fractionation was carried out. This chemotherapy regimen was repeated every 4 weeks for 2 years. MVP regimen (MTX 50 mg/m2) is now considered inadequate for PCNSL treatment, although high-dose MTX treatment was not common in these days.
From 1 August 1995 until 1 June 2003, we mainly used the ProMACE-MOPP hybrid protocol (12,13) (cyclophosphamide 650 mg/m2, pirarubicin 25 mg/m2, etoposide 120 mg/m2, vincristine 1.4 mg/m2, procarbazine 100 mg/m2, and prednisone 1 mg/kg) in association with MTX (500 mg/m2) for 32 patients. We also used leucorvorin rescue to prevent myelosuppression and other side effects. These agents were administered in 21-day cycles. Patients also underwent placement of an Ommaya reservoir, and 10 mg MTX was given for eight cycles once a week. After three cycles of chemotherapy, WBI at a total dose of 20 Gy with conventional fractionation was carried out. A single cycle of chemotherapy was repeated every 4 months for 2 years.
Our treatment policy was changed from 1 July 2003 until 30 June 2006, to the R-MTX regimen (20). From this time, we mainly used the R-MTX protocol (rituximab 375 mg/m2, MTX 1 g/m2, pirarubicin 25 mg/m2, procarbazine 100 mg/m2, and prednisone 1 mg/kg) for 11 patients. We also used leucorvorin rescue. These agents were administered in 21-day cycles. After three cycles of chemotherapy, WBI at a total dose of 20 Gy with conventional fractionation was carried out. Rituximab is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Rituximab has reported efficacy in PCNSL (21), since most PCNSLs express CD20.
Other therapies included steroid therapy without WBI (n = 3), cisplatin-based therapy (n = 3), vincristine-based therapy (n = 4), Ara-C-based therapy (n = 1), and another MTX-based therapy (n = 3) with WBI.
Salvage treatment for patients who received other regimens was individualized. In the irradiation regimen, 11 patients experienced their first recurrence in the CNS, and two received further radiotherapy. In the MVP regimen, 15 patients experienced their first recurrence in the CNS. Nine of these patients received salvage chemotherapy with MVP either alone (n = 3) or in combination (n = 6) with other cytotoxic drugs (such as cisplatin, cyclophosphamide, VP-16, nimustine, adriamycine, and vincristine), five of patients also received further irradiation. In the ProMACE-MOPP regimen, 15 patients experienced their first recurrence in the CNS. Eleven patients received salvage chemotherapy with ProMACE-MOPP either alone (n = 9) or in combination (n = 2) with other cytotoxic drugs (such as ara C, ranimustine, and rituximab), two patients also received further radiotherapy. In the R-MTX regimen, seven patients experienced their first recurrence in the CNS. All the seven patients received salvage R-MTX either alone (n = 2) or in combination (n = 5) with other cytotoxic drugs (such as ara C, ranimustine, rituximab cisplatin, and VP-16), and six patients also received further irradiation.
Staging Investigations Procedures
All patients underwent brain imaging with either computed tomography (CT) or magnetic resonance imaging (MRI). After the diagnostic biopsy, detailed history and physical examination, complete blood count, screening blood tests for hepatic and renal function, serum protein electrophoresis, and chest radiographs were obtained. CT or MRI of the thorax, abdomen, and pelvis was performed for all patients. Ophthalmologic consultations and slit-lamp examinations were employed to rule out ocular involvement. Bone marrow biopsy has not routinely been performed. Lumbar puncture for CSF evaluation was routinely performed.
Assessment of Early Toxicity and Late Neurotoxicity
Toxicity was graded using the National Cancer Institute Common Toxicity Criteria Version 3. Neurological symptoms due to late neurotoxicity were defined as those that appeared any time after completion of all treatment and could not be explained by other causes. A diagnosis of severe neurotoxicity was considered in those patients with progressive cognitive disorder that interfered with their lifestyle. A diagnosis of moderate neurotoxicity was one that precluded patients returning to work, but that did not interfere with basic activities of daily living or could return to work but with less stressing responsibilities. A diagnosis of normal was one that did not preclude them returning to work with stressing responsibilities. Diagnoses were carried out every 6 months 3 years after onset.
CT or MRI was reviewed by three of the authors. The scans were either CT in the axial plane or MRI with a T2W sequence. A grading system (0, normal; 1, minor; 2, mild; 3, moderate; 4, severe) was used in an attempt to evaluate the changes seen in: (a) ventricular size, (b) cortical atrophy, (c) leuco-encephalopathy (diffuse white matter disease), and (d) periventricular change (T2W high intense of periventricular area) (3,12). The average score obtained from the scan taken at the end of radiotherapy was used as the baseline, and compared with that of follow-up scans to determine whether there had been a change in grade. Every patient evaluated had the same type of scan at the end of radiotherapy and another scan at least once a year.
Statistical Methods
Two- and 5-year OS in patients was estimated. Categorical data were compared using the Fisher's exact test. Survival curves were estimated according to the Kaplan–Meier method. Logistic regression models were also used to identify clinically significant prognostic factors. On the basis of the results from univariate survival analyses and the logistic models, the Cox proportional hazard models were used to obtain a multiple prognosis factor model. Risk of relapse was determined from the date of complete response at the end of treatment to the time of relapse or the final visit. Survival was determined from the date of diagnosis to death or the final visit.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Patient Characteristics
The main patient characteristics are listed in Table 1. Ninety-four patients underwent a diagnostic biopsy procedure. In most patients, this was a stereotactic biopsy, 18 received partial removal and 4 total removal. For the 18 patients (16%) who did not undergo a diagnostic biopsy procedure, their diagnosis was based on radiographic appearance and CSF cytology. All 18 patients have detectable lesions and positive CSF-cytology with atypical lymphocyte. One patient was diagnosed by immunoglobulin gene rearrangement detected by a polymerase chain reaction (22). There was no impact of extent of surgical resection on neurological performance status and therapeutic outcome.
|
Treatment Completion
Although there were established treatment policies, some patients were not suitable for treatment with curative intent. Thus a small minority of patients (n = 3) received palliative treatment with steroids. For patients who were treated with the MVP regimen, the median number of cycles received was 8.1 (range, 1–24). For patients who were treated with the ProMACE-MOPP regimen, the median number of cycles received was 3.2 (range, 1–8). For patients who were treated with the R-MTX regimen, the median number of cycles received was 2.5 (range, 1–3). The median follow-up for all patients was 30 months. For the WBI, MVP, ProMACE-MOPP, and R-MTX groups, it was 20, 28, 60, and 14 months, respectively.
Treatment Failure
Seventy-nine of the 112 patients have since died. Of these patients, the cause of death was progressive lymphoma in 53. Eleven patients died of treatment-related toxicity, including five who died while receiving their primary treatment (four from pneumonia), and six patients died of neurocognitive impairment after diagnosis. Twelve patients died from other causes such as myocardial infarction or cerebral infarction. Three patients died from unknown causes. Seventy-one patients had treatment failures.
Survival
Median PFS and OS for the entire 112 patients were 18 and 24 months, respectively (Fig. 1). The 2- and 5-year actuarial probability of survival was 52.4 ± 4.8% [95% confidence intervals (CI)] and 30.2 ± 4.8% (95% CI), respectively (Fig. 1). Data were also analyzed according to the treatment administered, and the groups were subdivided into irradiation alone (n = 29) and combined-modality therapy with MVP (n = 26), ProMACE-MOPP (n = 32) or R-MTX (n = 11) (Table 2). OS as analyzed by treatment regimen is shown in Fig. 2. There was a statistically significant difference in OS between the ProMACE-MOPP regimen (500 mg/m2 MTX) and the WBI, MVP (50 mg/m2 MTX) groups (Fig. 2). To assess the contribution of MTX to OS, a separate analysis was undertaken that excluded three frail patients who received steroids only. We did this because it was believed that their poor outcomes were not informative. OS according to radiation dose [none (n = 16), 20–30 (n = 20), 30–40 (n = 38), and >40 (n = 28) Gy] is shown in Fig. 3. Doses of 20–30 Gy enhanced survival; however, doses over 30 Gy appeared not to. Univariate analysis demonstrated that six variables were significantly associated with OS [KPS, treatment regimen, whole- and local-brain radiation, treatment with MTX, and MTX dose (Table 3)]. Gender, age, intrathecal MTX administration, involvement of deep regions of the brain and solitary or multiple lesions were not significantly associated with OS. We verified assumptions for proportionality and used the Cox proportional model for multivariate analysis. Those variables that were significant in the univariate analysis were included in the multiple factor model. MTX dose, WBI doses and their squared dose were retained in the model (P = 0.015, <0.0001, 0.0002, respectively).
|
|
|
|
|
Early Treatment Toxicity
There was no Grade 3 or 4 toxicity in WBI and MVP groups. A total of 105 cycles of ProMACE MOPP were provided. The major acute toxicity was myelosuppression, with Grade 3 or 4 leucopenia documented in 33.3%, Grade 3 or 4 anemia in 2.8%, and Grade 3 or 4 thrombocytopenia in 10.4% of cycles. Thirty-nine cycles required the addition of G-CSF for hematologic toxicity with good recovery. There were eight Grade 3 or 4 pulmonary toxicities with two patients died. The other toxicity was hepatic (Grade 3: n = 4), and hyponatremia (Grade 3: n = 2; Grade 4: n = 1).
A total of 28 cycles of R-MTX were provided. The major acute toxicity was myelosuppression, with Grade 4 leucopenia documented in 3.5%, Grade 3 anemia in 3.5%, and Grade 3 thrombocytopenia in 17.8%. Six cycles required the addition of G-CSF for hematologic toxicity with good recovery. There were three Grade 3 pulmonary toxicities consisted of interstitial pneumonitis. The other toxicity was hepatic (Grade 3: n = 1), oral mucositis (Grade 3: n = 1), and infection without neutropenia (Grade 3: n = 2).
Late Therapy-Related Toxicity
Thus the clinical and CT or MRI results concerning possible late neurotoxicity in the 22 patients without relapse for >40 months were assessed (Table 4), although only a rough assessment is possible without psychometric tests.
|
Over the study period, severe neurotoxicity was recognized in 11 patients without relapse. These ranged in age from 51 to 72 years (median age, 64). In 10 of the 11 patients, treatment included WBI with >30 Gy. Severe neurotoxicity was recognized in 83% of these patients. By contrast, in patients receiving 20 Gy
WBI, severe neurotoxicity was recognized in only one patient (10%), while two patients, aged 58 and 73 years, had moderate neurotoxicity.
The presence of severe or moderate neurotoxicity was associated with a significant worsening of the imaging score after 2 years from the onset. Patients with no neurological deterioration after treatment showed a worsening of imaging score of 1.50 ± 2.12, compared with 6.27 ± 2.72 for patients with severe or moderate neurotoxicity (P< 0.01). Patients treated with 20 Gy WBI showed a worsening of imaging score of 1.90 ± 2.80, compared with 6.40 ± 2.31 for patients treated with 30 Gy 
WBI (P< 0.01).
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
In this study of 112 immunocompetent patients with PCNSL, the median OS was 24 months, and the 2- and 5-year survival rates were 52 and 30%, respectively. The median survival of this select group of patients, all of whom were well enough to receive MTX, was 50 months, which is comparable to the survival reported in published Phase II clinical trials (6,10,15,23).
The dosage of WBI may be important for tumor control, as well as related to the development of neurotoxicity. Neurotoxicity in patients who receive more than 40 Gy irradiation has been found to be substantial, especially in those aged >60 years (6,8,10,13,14). All 11 patients who suffered severe dementia received WBI (median dose, 32 Gy). The median age of these patients was 63 years. No neurocognitive impairment was recorded in a younger group of patients (median age, 52 years) who received a lower median dose of WBI (20 Gy). In patients aged >60 years, some studies have shown that the WBI dose is a risk factor for neurotoxicity (4,15). Our data suggested that more severe neurocognitive impairment is seen with increasing age and WBI dose.
HD-MTX with radiation therapy might also produce significant cognitive problems with a 25–75% overall incidence of late toxicity after prolonged follow-up (11,13,15). For patients aged >60 years the risk of neurotoxicity is 58–75% (8,11). Preservation of cognitive function appears to be better after chemotherapy alone (24,25) and there are increasing reports (8,23,25–27) showing radiotherapy to be deferred after chemotherapy. There are conflicting data that chemotherapy alone is an effective alternative for many patients with PCNSL; some authors have reported prolonged disease control, but others have noted frequent tumor progression (7,15,27,28). Subclinical MTX-induced white matter disease has been reported in patients treated with HD-MTX. In our study, the incidence of neurotoxicity was relatively low in patients treated with <20 Gy irradiation. The preservation of cognitive function in most patients treated with 20 Gy WBI compares favorably with the 83% of patients who developed dementia when treated with >30 Gy WBI. Six patients who died of neurocognitive impairment after diagnosis had been treated with >30 Gy WBI. Higher doses (>30 Gy) were not superior to intermediate (20–30 Gy) WBI doses for survival of patients. This means that we cannot treat patients with PCNSL by higher WBI doses alone. Patients treated with higher WBI doses have higher risk of death of neurocognitive impairment. Moderate doses of MTX and low-dose radiotherapy may significantly reduce the chances of neurocognitive toxicity.
In conclusion, although this study has the limitations as patients were selected for inclusion retrospectively and there was significant treatment and assessment heterogeneity over this 24-year interval, patients who received MTX showed a better survival than those who received WBI alone. Patients who received MTX can be treated with a 20 Gy WBI without compromising their OS or inducing severe neurotoxicity. A modest dose of MTX followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity. Further efforts must be directed at reducing the neurologic sequelae of such treatment. However, a regimen that will result in improved survival rates with a low rate of late side effects for patients with PCNSL remains to be developed.
Conflict of interest statement
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg (1998) 68:835–53.
2 Bessell EM, Graus F, Punt JA, Firth JL, Hope DT, Moloney AJ, et al. Primary non-Hodgkin's lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. J Clin Oncol (1996) 14:945–54.
3 Bessell EM, Graus F, Lopez-Guillermo A, Villa S, Verger E, Petit J, et al. CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys (2001) 50:457–64.[CrossRef][Web of Science][Medline]
4 Bessell EM, Lopez-Guillermo A, Villa S, Verger E, Nomdedeu B, Petit J, et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol (2002) 20:231–6.
5 DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol (1992) 10:635–43.
6 DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol (2002) 20:4643–8.
7 Freilich RJ, Delattre JY, Monjour A, DeAngelis LM. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology (1996) 46:435–9.
8 Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol (2006) 24:4570–4.
9 Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg (1994) 81:188–95.[Web of Science][Medline]
10 O'Brien P, Roos D, Pratt G, Liew K, Barton M, Poulsen M, et al. Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol (2000) 18:519–26.
11 O'Brien PC, Roos DE, Pratt G, Liew KH, Barton MB, Poulsen MG, et al. Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group). Int J Radiat Oncol Biol Phys (2006) 64:408–13.[Web of Science][Medline]
12 Yamanaka R, Morii K, Shinbo Y, Takeuchi S, Tamura T, Hondoh H, et al. Modified ProMACE-MOPP hybrid regimen with moderate dose methotrexate for patients with primary CNS lymphoma. Ann Hematol (2005) 84:447–55.[CrossRef][Web of Science][Medline]
13 Yamanaka R, Shinbo Y, Sano M, Homma J, Tsuchiya N, Yajima N, et al. Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen. Leuk Lymphoma (2007) 48(6):1119–26.[CrossRef][Web of Science][Medline]
14 Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol (1998) 16:859–63.[Abstract]
15 Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol (2000) 18:3144–50.
16 Omuro AM, Ben-Porat LS, Panageas KS, Kim AK, Correa DD, Yahalom J, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol (2005) 62:1595–600.
17 National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas. Summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer (1982) 49:2112–35.[CrossRef][Web of Science][Medline]
18 Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A Revised European-American Classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood (1994) 84:1361–92.
19 Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol (1999) 10:1419–32.
20 Yamanaka R, Homma J, Sano M, Tsuchiya N, Yajima N, Shinbo Y, et al. Immuno-chemotherapy with a combination of rituximab, methotrexate, pirarubicin and procarbazine for patients with primary CNS lymphoma- a preliminary report. Leuk Lymphoma (2007) 48(5):1019–22.[CrossRef][Web of Science][Medline]
21 Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology (2004) 63:901–3.
22 Endo S, Zhang SJ, Saito T, Kouno M, Kuroiwa T, Washiyama K, et al. Primary malignant lymphoma of the brain: mutation pattern of rearranged immunoglobulin heavy chain gene. Jpn J Cancer Res (2002) 93:1308–16.[CrossRef][Web of Science]
23 Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol (2003) 21:1044–9.
24 Schlegel U, Pels H, Glasmacher A, Kleinschmidt R, Schmidt-Wolf I, Helmstaedter C, et al. Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study. J Neurol Neurosurg Psychiatry (2001) 71:118–22.
25 Neuwelt EA, Goldman DL, Dahlborg SA, Crossen J, Ramsey F, Roman-Goldstein S, et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol (1991) 9:1580–90.[Abstract]
26 Cher L, Glass J, Harsh GR, Hochberg FH. Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology (1996) 46:1757–9.
27 Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, et al. Primary central nervous system lymphoma: results of a pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy. J Clin Oncol (2003) 21:4489–95.
28 Herrlinger U, Schabet M, Brugger W, Kortmann RD, Kuker W, Deckert M, et al. German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma. Ann Neurol (2002) 51:247–52.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||