Kasenda B, Haug V, Schorb E, et al.
18F-FDG PET is an independent outcome predictor in primary central nervous system lymphoma.
J Nucl Med. 2013; 54(2):184-91 [PubMed]

UNLABELLED: Primary central nervous system (CNS) lymphoma is an aggressive non-Hodgkin lymphoma with poor prognosis. We evaluated pretreatment (18)F-FDG PET as a prognostic marker in primary CNS lymphoma.
METHODS: Forty-two immunocompetent patients with newly diagnosed primary CNS lymphoma who underwent pretreatment (18)F-FDG PET were retrospectively analyzed. Baseline status and response to treatment were evaluated by MR imaging. Tumor maximum standardized uptake values were assessed by volume-of-interest analyses using an automatic isocontour definition. A 10-step semiquantitative visual rating system (metabolic imaging lymphoma aggressiveness scale, or MILAS) was used to assess primary CNS lymphoma metabolism as a marker of clinical aggressiveness. Logistic regression, log-rank testing, and multivariable Cox regression were used to investigate the association between (18)F-FDG uptake and tumor response and survival.
RESULTS: Mean maximum standardized uptake value correlated linearly with MILAS. The distribution of patients according to MILAS (0-9) was 0%, 28.6%, 23.8%, 21.4%, 11.9%, 4.8%, 7.1%, 0%, 0%, and 2.4%. There was no correlation between MILAS and response to treatment. Respective 2- and 5-y survival rates were 52% and 32% for progression-free survival (PFS) and 64% and 50% for overall survival (OS). A cutoff at MILAS 3 was a good separator for PFS (median: 54.7 mo [≤3], 3.8 mo [>3], P = 0.0272) and OS (median: not reached [≤3], 13.8 mo [>3], P = 0.131). In multivariable analyses, increasing MILAS was significantly associated with shorter PFS (hazard ratio, 1.49, P = 0.006) and OS (hazard ratio, 1.43, P = 0.018).
CONCLUSION: Increased pretreatment (18)F-FDG uptake may offer new opportunities for baseline risk evaluation in untreated primary CNS lymphoma.

Yoon JH, Kang HJ, Kim H, et al.
Successful treatment of primary central nervous system lymphoma without irradiation in children: single center experience.
J Korean Med Sci. 2012; 27(11):1378-84 [PubMed] Free Access to Full Article

Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Children's Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.

Bergner N, Monsef I, Illerhaus G, et al.
Role of chemotherapy additional to high-dose methotrexate for primary central nervous system lymphoma (PCNSL).
Cochrane Database Syst Rev. 2012; 11:CD009355 [PubMed]

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that accounts for about 2% to 5% of all primary intracranial tumours with immunocompetent patients. It appears at a median age of 62 years. A standard of care for PCNSL patients has not been defined yet, but high-dose methotrexate (HD-MTX) is considered to be a beneficial chemotherapy in PCNSL treatment. Currently, HD-MTX is combined with numerous other chemotherapy drugs to improve outcomes of HD-MTX monotherapy. However, the impact of additional chemotherapy remains unclear, as there is evidence of a higher risk of adverse events (AEs) such as infective complications.
OBJECTIVES: We performed a systematic review of randomised controlled trials (RCTs) to assess the efficacy and safety of additional chemotherapy to HD-MTX in the treatment of immunocompetent PCNSL patients.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) and MEDLINE (from 1950 to May 2012) as well as conference proceedings for RCTs. Two review authors (NB, NS) independently screened search results.
SELECTION CRITERIA: We included RCTs comparing HD-MTX in combination with additional chemotherapy to mono-chemotherapy with HD-MTX in immunocompetent patients off all ages in first-line treatment of PCNSL.
DATA COLLECTION AND ANALYSIS: As an effect measure we used hazard ratios (HR) and 95% confidence intervals (CI) for overall survivals (OS) and progression-free survival (PFS). For effect measure of complete remission rate (CRR), partial response rate (PRR), treatment-related mortality (TRM) and AEs we used risk ratios (RR). Two review authors (NB, NS) independently extracted data and assessed the quality of trials.
MAIN RESULTS: Our search strategies led to 699 potentially relevant references. Of these, one RCT involving 79 patients was included. We judged the quality of the trial as moderate. The study was reported as a randomised open-label study and published as a full-text article.Even though PFS was statistically significantly improved for patients treated with HD-MTX plus cytarabine (HR 0.54; 95% CI 0.31 to 0.92; P = 0.01), this did not translate to a statistical significant OS benefit (HR 0.65; 95% CI 0.38 to 1.13; P = 0.07). AEs, especially infective complications, hepatotoxicity and haematological toxicities, were assessed more often in patients undergoing HD-MTX therapy combined with cytarabine. However, there were no statistically significant differences in terms of TRM (RR 3.08; 95% CI 0.33 to 28.32; P = 0.35).
AUTHORS' CONCLUSIONS: Owing to the small number of included trials and patients, the findings in this review remain uncertain. In summary, the presently available evidence (one small trial) showed a benefit in terms of PFS, ORR and CRR but no statistically significant difference regarding OS for patients with PCNSL treated with HD-MTX plus cytarabine compared to HD-MTX alone. However, the risk of severe infections and toxicity was significantly higher in patients treated with combined chemotherapy. More RCTs with additional chemotherapy to HD-MTX therapy with higher numbers of patients and longer follow-up periods are needed to confirm the results of this review and determine whether the PFS benefit will translate into an OS advantage. At least the one included study shows that RCTs of moderate quality and with valuable outcomes for this malignant disease are feasible.

Linnebank M, Moskau S, Kowoll A, et al.
Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.
Br J Cancer. 2012; 107(11):1840-3 [PubMed] Article available free on PMC after 20/11/2013

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients.
METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol).
RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis.
CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

Yuan J, Gu K, He J, Sharma S
Preferential up-regulation of osteopontin in primary central nervous system lymphoma does not correlate with putative receptor CD44v6 or CD44H expression.
Hum Pathol. 2013; 44(4):606-11 [PubMed]

Osteopontin (SPP1) is reportedly the most up-regulated gene in primary central nervous system lymphoma (PCNSL). Our objective was to confirm immunoexpression of osteopontin and determine if CD44v6 and CD44H played a significant role as receptors for osteopontin in PCNSL. Twenty PCNSL, 12 nodal diffuse large B-cell lymphoma (N-DLBCL), and 17 extra-nodal DLBCL (EN-DLBCL) archival pathology cases were examined. Osteopontin nuclear positivity was observed in 20 (100%) of 20 PCNSL cases, 16 (95 %) of 17 EN-DLBCL, and 3 of 12 (25%) N-DLBCL. The immunohistochemical score of osteopontin in PCNSL (7.0 ± 3.5) and EN-DLBCL (4.4 ± 4.1) was significantly higher than N-DLBCL (0.3 ± 0.6). Sixteen cases were positive for CD44v6 (33%), including 6 PCNSL, and 5 each EN-DLBCL and N-DLBCL; no statistical difference was observed. CD44H was positive in all cases except one PCNSL but without any significant differences across the 3 groups. CD44H expression was significantly higher in non-germinal center B-cell (GCB) (score 12 ± 1.5) as compared to the GCB group (9.5 ± 3.1), and in non-GCB PCNSL (7.9 ± 4.2) as compared to non-GCB non-CNS lymphoma (2.8 ± 4.0) (P = .009); the differences were insignificant for osteopontin and CD44v6. Neither CD44H nor CD44v6 scores correlated with the osteopontin expression score or Ki-67 index. Osteopontin immunoexpression was highest in PCNSL, suggesting its probable role in its pathogenesis. However, its lack of correlation with CD44v6 excludes the latter as the likely osteopontin receptor in PCNSL. The significantly higher CD44H expression in the non-GCB than GCB group may contribute to the aggressiveness of the non-GCB DLBCL. Further studies are needed to elucidate the pathway and the prognostic/predictive role of osteopontin in PCNSL.

Schäfer N, Glas M, Herrlinger U
Primary CNS lymphoma: a clinician's guide.
Expert Rev Neurother. 2012; 12(10):1197-206 [PubMed]

Primary CNS lymphoma is a high malignant disease of the brain which can lead rapidly to death if diagnosis and/or the start of treatment is delayed. The age at time of diagnosis is a strong factor influencing prognosis so that in younger patients <65 years of age long-term survival may be achieved in a substantial percentage of patients, while in elderly patients long-term survival is seen much more rarely. First-line therapy consists of high-dose methotrexate-based (poly)chemotherapy. This review provides an overview of clinical presentation, steps to diagnosis, detailed information about current treatment concepts and specific information for particular clinical situations.

Wong SF, Gan HK, Cher L
A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide.
J Clin Neurosci. 2012; 19(11):1501-5 [PubMed]

Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. Although recommendations for first-line treatment usually incorporate high-dose methotrexate, there is substantial heterogeneity in the types of salvage therapies used at relapse. Phase II data supported the use of temozolomide as a well-tolerated treatment modality in this setting. Therefore, we reviewed the treatment and outcomes of patients with relapsed PCNSL who were treated with salvage temozolomide at our institution. Seven patients were treated with salvage temozolomide between January 2000 and May 2011. The objective response rate was 14%. Progression-free survival was 2 months (95% confidence interval [CI]: 0-5.9) and median overall survival was 4 months (95% CI: 0-13). Toxicity was mild, with one episode of grade 3 neutropenia during 25 cycles of chemotherapy. Although these results are consistent with previous phase II results, the outcomes for these patients remain extremely poor. The low toxicity of temozolomide raises the possibility of combining temozolomide with other chemotherapeutic agents or targeted agents in future clinical trials.

Osmani AH, Masood N
Temozolomide for relapsed primary CNS lymphoma.
J Coll Physicians Surg Pak. 2012; 22(9):594-5 [PubMed]

Primary CNS lymphoma (PCNSL) is an aggressive form of non-Hodgkin's lymphoma that accounts for 3% of all primary brain tumours. No clear risk factors for PCNSL in immunocompetent patients are known. The disease is more common in men and in elderly persons. Patients with AIDS who have low CD4+ counts are at the greatest risk for PCNSL. Virtually all PCNSLs in patients with AIDS express an Epstein-Barr virus (EBV)-related genome. PCNSL is less frequently associated with EBV in patients without AIDS. A 42 years old gentleman diagnosed with primary CNS lymphoma with negative serological test for human immunodeficiency virus was initially treated with Modified De Angelis protocol relapsed after treatment. He underwent gamma knife stereotactic surgery which lead to further deterioration clinically and progression of disease on imaging. Later, he was treated with salvage high dose methotrexate, but after completion of six cycles there was a radiological progression of disease. Relapsed disease was further treated with a single agent temozolomide and the disease went in remission.

Welch MR, Omuro A, Deangelis LM
Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center.
Neuro Oncol. 2012; 14(10):1304-11 [PubMed] Article available free on PMC after 01/10/2013

Up to 20% of all primary CNS lymphoma (PCNLS) patients are aged 80 years or older, yet data are limited on how best to treat this rapidly growing population. Despite demographic pressures and the proven efficacy of methotrexate (MTX)-based regimens, automatic de-escalation of care based on age is standard practice outside of tertiary care centers. We performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011. Demographic and clinical variables were evaluated as predictors of survival by multivariate analysis. Twenty-three of 24 patients were treated with chemotherapy (92% with high-dose MTX, typically in combination with vincristine and procarbazine). One patient received ocular radiation alone for disease limited to the eyes. Response to treatment was noted in 62.5% of patients; 9 (37.5%) had refractory disease. Median overall survival was 7.9 months (95% confidence interval [CI]: 5.8-53), and median progression-free survival was 6.5 months (95% CI: 4.4-29.5). Two-year survival rate was 33%; 3-year survival rate was 17%. Three patients lived more than 4 years postdiagnosis. Most patients tolerated therapy well, and despite low baseline creatinine clearance, no significant renal toxicity was noted. Response status and deep brain involvement were identified as the most important predictors of survival. Multidrug regimens containing high-dose MTX are feasible and efficacious among the oldest patients, particularly those who achieve a complete response by their fifth treatment cycle. Aggressive therapy should be offered to select patients irrespective of advanced age.

Roth P, Martus P, Kiewe P, et al.
Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial.
Neurology. 2012; 79(9):890-6 [PubMed]

OBJECTIVE: To assess the outcome of elderly patients with primary CNS lymphoma (PCNSL) treated within the G-PCNSL-SG-1 trial.
METHODS: We reviewed response, toxicity, and survival of patients with PCNSL aged 70 or more enrolled in the G-PCNSL-SG-1 trial.
RESULTS: A total of 126 of the 526 eligible patients (24%) and 66 of 318 patients (21%) in the per protocol population were aged 70 or more. Among all eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly vs 57% in the younger patients (p = 0.016). Toxicity was age-independent except for a higher rate of grade III/IV leukopenia in the elderly (34% vs 21%, p = 0.007). Death on therapy was more frequent (18% vs 11%; p = 0.027), and progression-free survival (PFS) (4.0 vs 7.7 months, p = 0.014) and overall survival (12.5 vs 26.2 months, p < 0.001) inferior, in the elderly. A striking difference between younger and elderly patients was the PFS of CR patients of 35.0 in the younger vs 16.1 in the elderly patients (p = 0.024). Elderly patients were treated less often and less aggressively at salvage. However, age was not associated with survival from salvage whole brain radiotherapy in patients progressing during primary HD-MTX-based chemotherapy (p = 0.633).
CONCLUSIONS: Lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL.

Rosenfeld MR, Pruitt AA
Management of malignant gliomas and primary CNS lymphoma: standard of care and future directions.
Continuum (Minneap Minn). 2012; 18(2):406-15 [PubMed]

PURPOSE OF REVIEW: This article review the current standard of care of astrocytic gliomas and primary CNS lymphoma and discusses promising new therapeutic targets.
RECENT FINDINGS: Standard treatment modalities for primary malignant brain tumors include resection, radiation, local or systemic chemotherapy, and, most recently, antiangiogenic agents. However, these tumors often have a rapid course, and patients usually die within a few years of diagnosis. Improved surgical techniques and radiation and chemotherapy can prolong survival while maintaining quality of life, but these therapies remain inadequate.
SUMMARY: The care of patients with malignant brain tumors is challenging. A better understanding of the pathogenesis of primary malignant brain tumors and the elucidation of aberrant molecular pathways are leading to novel treatment strategies and the ability to identify patients who may benefit from specific treatments.

Brastianos PK, Batchelor TT
Primary central nervous system lymphoma: overview of current treatment strategies.
Hematol Oncol Clin North Am. 2012; 26(4):897-916 [PubMed]

Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive variant of non-Hodgkin lymphoma that involves the brain, eyes, leptomeninges, or spinal cord. Therapeutic progress has been modest, and our understanding of the molecular mechanisms that drive this disease is limited. Clinicians treating PCNSL face a challenge to balance the need to administer aggressive regimens to achieve a cure with the risks of delayed neurotoxicity after treatment. The standard treatment is a methotrexate-containing chemotherapy regimen. The timing and dose of whole-brain radiation therapy is controversial, given the significant risks of late neurotoxic effects, particularly in elderly patients.

Teo MK, Mathieson C, Carruthers R, et al.
Cauda equina lymphoma--a rare presentation of primary central nervous system lymphoma: case report and literature review.
Br J Neurosurg. 2012; 26(6):868-71 [PubMed]

The spinal cord is an extremely rare site for primary central nervous system (CNS) lymphoma (< 1%). Very few cases of primary cauda equina (including conus) lymphoma were previously reported. We report such a case, and with literature review, discuss their clinical features, operative and histopathological findings. Although rare, with an increasing incidence of CNS lymphoma, they should be considered in the differential diagnosis of intradural lesions. Furthermore, with intraoperative smear to establish diagnosis, extensive surgery can be avoided. The controversial role of glucocorticoids in the management of these patients is also discussed.

Prica A, Chan K, Cheung MC
Combined modality therapy versus chemotherapy alone as an induction regimen for primary central nervous system lymphoma: a decision analysis.
Br J Haematol. 2012; 158(5):600-7 [PubMed]

In immunocompetent patients with primary central nervous system (CNS) lymphoma, combined modality therapy (CMT) using high-dose methotrexate and whole brain radiotherapy has improved response rates compared to chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity. A Markov decision-analytic model compared CMT to chemotherapy alone in patients with primary CNS lymphoma. Baseline probabilities were derived from a systematic literature review. Outcomes were life expectancy and quality-adjusted life expectancy. Sensitivity analyses were performed. The life expectancy was 2·69 years for CMT and 2·77 years for chemotherapy alone. The quality-adjusted life expectancies for the two strategies were 1·70 and 1·67 quality-adjusted life years (QALYs) respectively. In younger patients <60 years of age, CMT yielded a quality-adjusted life expectancy of 2·71 QALYs, compared to 2·09 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0·62 QALYs or 7·4 quality-adjusted months. There was no difference between the strategies in the older group. The model was robust to key variables for the younger group. The preferred induction strategy for younger patients appears to be CMT, maximizing life expectancy, and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone.

Baraniskin A, Kuhnhenn J, Schlegel U, et al.
MicroRNAs in cerebrospinal fluid as biomarker for disease course monitoring in primary central nervous system lymphoma.
J Neurooncol. 2012; 109(2):239-44 [PubMed]

Diagnosis of primary lymphomas of the central nervous system (PCNSL) largely depends on histopathology of tumor biopsies. Recently, we identified miRNAs detected in the CSF of PCNSL patients as novel non-invasive biomarkers for this disease. In combined analyses of miR-21, miR-19b, and miR-92 CSF levels, it was possible to differentiate PCNSL from other neurological disorders. In the current study, we first confirmed our previous findings in an enlarged PCNSL cohort (n = 39; sensitivity 97.4 %). Also, we sought to establish the potential role of CSF miRNAs as biomarkers for disease course monitoring. In sequential miRNA measurements in CSF derived from nine patients with different disease courses, an intriguing correlation of miRNA levels and PCNSL status during treatment and/or disease follow-up was demonstrated. Finally, we demonstrated that miRNA levels in serum of PCNSL patients (n = 14) were not elevated as compared to controls. In summary, this study provides the first evidence that CSF miRNAs have the potential as biomarkers for treatment monitoring and disease follow-up of patients with PCNSL.

Sutherland T, Yap K, Liew E, et al.
Primary central nervous system lymphoma in immunocompetent patients: a retrospective review of MRI features.
J Med Imaging Radiat Oncol. 2012; 56(3):295-301 [PubMed]

UNLABELLED: INTRODUCTIon: To define the features of primary central nervous system lymphoma (PCNSL) on MRI in immunocompetent patients.
METHODS: A retrospective review of the authors' institutional database was performed to identify histologically proven cases of PCNSL. Images were retrieved and reviewed with respect to location, lesion number, size, signal intensity, enhancement characteristics, oedema and necrosis.
RESULTS: Thirty-one cases of histologically proven PCNSL had available imaging. One patient was excluded due to immunosuppression. Of the 30 remaining cases, the average age was 65.5 years, and males and females were equally represented. A total of 68 lesions (average of 2.5 per patient) were identified. With diffusion-weighted imaging, all but two had restricted diffusion (40.3% mild and 55.6% marked) and all but one had enhancement (51.5% homogeneous, 42.6% heterogeneous and ring 4.4%). Most lesions were isointense to grey matter (75.8% on T2-weighted image (WI) and 82.5% on T1-WI). Oedema was mild in 43.4% and marked in 55.2%. Necrosis was seen in only five lesions (7.4%). On a per patient basis, 50% had bilateral lesions and 96.7% had lesions contacting a cerebrospinal fluid (CSF) surface. 16.7% of patients had posterior fossa involvement and 30% had lesions in the basal ganglia or thalami.
CONCLUSION: The vast majority of cases of PCNSL in immunocompetent patients have lesions contacting a CSF surface, enhancement and restricted diffusion with no necrosis. These features should alert radiologists to the diagnosis of PCNSL.

Sasakawa A, Hirase C, Yamaguchi T, et al.
Interleukin-8 in the pathogenesis of primary central nervous system lymphoma in association with HIV infection.
Hematology. 2012; 17(3):144-50 [PubMed]

The pathogenesis of acquired immunodeficiency syndrome-associated primary central nervous system lymphoma (AIDS-associated PCNSL) remains unclear. However, cell adhesion molecules have been reported to be strongly associated with PCNSL. In this study, we established Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) from HIV-positive patients (LCL(HIV)) and normal individuals (LCL(N)). The expression of CD18 antigen by LCL(HIV) was stronger than that by LCL(N). We performed a cell adhesion assay using ISO-HAS, which is the human hemangiosarcoma cell line and expresses intercellular adhesion molecule 1 (CD54). The binding rates of LCL(HIV) and ISO-HAS without stimulation were higher than those of LCL(N). Further, we demonstrated that azidothymidine or simvastatin inhibited the binding rates of LCL(HIV) and ISO-HAS more significantly than those of LCL(N). Further, the levels of interleukin (IL)-8, a CD18 inducer, were higher in LCL(HIV) than in LCL(N). We conclude that interaction between IL-8 and CD18 may be critical to AIDS-related PCNSL.

Nayak L, Abrey LE, Drappatz J, et al.
Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma.
Leuk Lymphoma. 2013; 54(1):58-61 [PubMed]

We initiated a prospective multicenter phase II trial using rituximab and temozolomide in immunocompetent patients with progressive or recurrent primary central nervous system lymphoma (PCNSL) based on activity observed in retrospective studies. Treatment consisted of an induction phase with rituximab (750 mg/m(2)) on days 1, 8, 15 and 22 and temozolomide (150 mg/m(2)) days 1-7 and 15-21, followed by six cycles of consolidation temozolomide (150-200 mg/m(2) × 5/28 days), followed by maintenance with methylprednisolone (1 g IV every 28 days) until progression. Sixteen patients were enrolled, and a complete response was seen in 2/14 (14%) evaluable patients. The median progression-free survival was 7 weeks and median overall survival was not reached (median follow-up: 37 months). Treatment was well tolerated, but due to slow accrual and preliminary analysis suggesting futility, the trial was closed early. Given the overall modest activity, this regimen should be reserved for patients who are not candidates for other, more aggressive salvage treatments.

Roth P, Korfel A, Martus P, Weller M
Pathogenesis and management of primary CNS lymphoma.
Expert Rev Anticancer Ther. 2012; 12(5):623-33 [PubMed]

Primary CNS lymphoma (PCNSL), a rare variant of extranodal non-Hodgkin's lymphoma, may cause various neurological symptoms and signs. The best therapeutic strategy is still a matter of debate. High-dose methotrexate (HD-MTX) is the most active compound and should be used as the backbone for any chemotherapy applied. Several other chemotherapeutic drugs have been assessed in combination with HD-MTX, but no standard has yet been defined. Whole-brain radiotherapy is active against PCNSL, but typically does not confer long-lasting remission and is associated with significant neurotoxicity in many patients. The recently published G-PCNSL-SG1 trial has shown that consolidating whole-brain radiotherapy after HD-MTX-based chemotherapy does not prolong overall survival and may therefore be deferred. Combined systemic and intraventricular polychemotherapy, or high-dose chemotherapy followed by stem cell transplantation may offer cures to younger patients. Improving treatment regimens without adding significant (neuro-)toxicity should be the focus of ongoing and future studies.

Liu L, Zheng Y, Lu H
Development of primary central nervous system lymphoma in an HIV-infected patient after multiple opportunistic infections.
Int J STD AIDS. 2012; 23(3):e41-5 [PubMed]

A 35-year-old Chinese man presented to medical attention with fever, cough and shortness of breath and HIV infection. His CD4+ lymphocyte count was 28 cells/μL and his HIV viral load was 386,891 copies/mL. Diagnosis of tuberculosis, Pneumocystis jiroveci pneumonia, mycobacterium avium complex, fungal infection and cytomegalovirus retinitis were confirmed according to the symptoms, laboratory results and radiology. After therapy for all these opportunistic infections, his symptoms were relieved. In addition, highly active antiretroviral therapy (HAART) was also initiated two weeks after his admission. The patient had a headache two months after admission and the magnetic resonance image of the brain showed left frontal lobe hypodensity. The patient then accepted brain biopsy and the pathological result proved to be primary central nervous system lymphoma). The patient refused further therapy and lost in our follow-up.

Yamamoto T, Kojima K, Koibuchi K, et al.
A case of primary central nervous system lymphoma presenting diffuse infiltrative leukoencephalopathy.
Intern Med. 2012; 51(9):1103-6 [PubMed]

A 58-year-old immunocompetent man gradually developed loss of appetite, cognitive decline, gait disturbances, and personality changes over 4 months. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without mass formation on admission. His condition progressively deteriorated, and we treated him with intravenous high-dose steroids. His symptoms improved rapidly, but exacerbated when therapy was withdrawn. A brain biopsy was performed, and the diagnosis of primary central nervous system lymphoma (PCNSL) was confirmed. He was successfully treated with high-dose methotrexate therapy. Although it is difficult to diagnose PCNSL without mass formation in the early stages, steroid responsiveness is important and brain biopsy is essential for the correct diagnosis of PCNSL.

Birnbaum T, Stadler EA, von Baumgarten L, Straube A
Rituximab significantly improves complete response rate in patients with primary CNS lymphoma.
J Neurooncol. 2012; 109(2):285-91 [PubMed]

Rituximab improves outcome for patients with systemic diffuse large B-cell lymphoma (DLBCL) and has therefore become a standard component of the treatment of this disease. However, it is unclear whether rituximab is efficacious in patients with primary CNS lymphoma (PCNSL), a rare DLBCL variant, also. The purpose of this study was to evaluate the effect of rituximab on the complete response (CR) rate after chemotherapy with methotrexate (MTX) and ifosfamide (IFO) of patients with PCNSL. This is a retrospective, observational, single-center trial analyzing 36 consecutive patients with newly diagnosed, CD-20-positive PCNSL who were treated primarily with chemotherapy between March 2007 and December 2010. We compared 19 patients who were treated with MTX and IFO with 17 patients who were treated with the same regimen plus rituximab. The addition of rituximab to MTX and IFO was correlated with a significant increase in the CR rate (100.0 vs. 68.4 %, p = 0.02). Furthermore, six-month progression-free survival was significantly higher for the rituximab group (94.1 vs. 63.2 %, p = 0.04). Toxicity did not differ significantly between the groups. Our results indicate that rituximab might be efficacious in the treatment of PCNSL and support addition of this drug to current treatment protocols until data from randomized controlled trials becomes available. Immunochemotherapy with MTX, IFO, and rituximab seems to have excellent activity as induction chemotherapy and should be further tested in prospective trials.

Joerger M, Huitema AD, Illerhaus G, Ferreri AJ
Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma.
Leuk Lymphoma. 2012; 53(10):1867-75 [PubMed]

Methotrexate (MTX) at a dose of ≥1 g/m(2) remains the most efficient treatment against primary central nervous system lymphoma (PCNSL), and is the most widely used drug in prospective clinical trials. MTX is a folate analog that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. MTX as well as 7-hydroxy-MTX, its main metabolite in serum, are both eliminated by the kidneys. The elimination of MTX is prolonged in patients with renal impairment and third-space fluid collections, and in patients receiving concurrent non-steroidal antirheumatic drugs, benzimidazoles and sulfonamides, among others. Main adverse events with high-dose MTX include severe myelosuppression, renal dysfunction and stomatitis. Supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are crucial to avoid significant toxicity. Strategies to optimize clinical efficacy of high-dose MTX in patients with PCNSL include administration of 3 h instead of longer infusions, potentially supplemented with an additional intravenous MTX bolus, and maintaining MTX dose intensity over the course of four treatment cycles. Some pharmacological studies suggest that achieving an MTX area under the plasma concentration-time curve (AUC(MTX)) of between 1000 and 1100 μmol.h/L may improve clinical outcome, but clinical data are not conclusive at present. In this review, we analyze the impact of patient, lymphoma and pharmacokinetic variables on the antitumor activity of high-dose MTX in patients with PCNSL, summarize recommendations for daily clinical practice and give some suggestions for future trials.

Yap KK, Sutherland T, Liew E, et al.
Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay.
J Med Imaging Radiat Oncol. 2012; 56(2):179-86 [PubMed]

Primary central nervous system lymphoma (PCNSL) is an uncommon but important variant of non-Hodgkin lymphoma and represents up to 6% of all primary central nervous system (CNS) malignancies. Recognition of this entity by radiologist on MRI may avoid unnecessary neurosurgical resection and redirect to biopsy. The pretreatment MRI of patients with biopsy proven PCNSL from the last 5 years at our institution was reviewed. Selected examples were used to construct a pictorial essay to illustrate some of the typical and atypical MR features of PCNSL. MRI of other CNS conditions with imaging similarities to PCNSL was included to demonstrate possible mimics. The typical features of PCNSL lymphoma are intra-axial homogenous single or multiple contrast enhancing lesions, with marked surrounding oedema and restricted diffusion, usually contacting a cerebrospinal fluid (CSF) surface. Necrosis, peripheral enhancement, haemorrhage or calcification are unusual and other diagnoses should be considered if any of these features are present. Potential mimics include high grade glioma, infarcts, metastatic disease, demyelination, abscess and secondary lymphoma. Careful assessment of the MR features and correlation with the clinical findings should enable the radiologists to raise the possibility of PCNSL and minimise the risk of unnecessary resection.

Kasenda B, Schorb E, Fritsch K, et al.
Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study.
Ann Oncol. 2012; 23(10):2670-5 [PubMed]

BACKGROUND: High-dose chemotherapy followed by autologous stem-cell transplantation (HCT-ASCT) is a promising approach in eligible patients with primary central nervous system lymphoma (PCNSL). We report long-term data of patients who were treated according to HCT-ASCT containing protocols.
PATIENTS AND METHODS: We analyzed survival and relapse rates in 43 (<67 years) immunocompetent patients with newly diagnosed PCNSL being treated according to two different high-dose methotrexate-based protocols followed by high-dose carmustine/thiotepa (BCNU/TT) plus ASCT (±whole brain irradiation). Analysis was conducted for all patients (intention-to-treat) and those patients who actually received HCT-ASCT (per-protocol).
RESULTS: Thirty-four patients achieved complete remission, of those 12 relapsed (35%), while 6 of them relapsed 5 years after diagnosis. After a median follow-up of 120 months, median overall survival (OS) was reached after 104 months. Two- and 5-year OS was 81% and 70% and 2- and 5-year event-free survival (EFS) was 81% and 67%, respectively. In per-protocol analysis (N = 34), 5-year OS and EFS was 82% and 79%, respectively. HCT-ASCT associated related mortality was not observed.
CONCLUSIONS: Sequential high-dose MTX containing chemotherapy followed by high-dose carmustine/thiotepa plus ASCT (±whole brain irradiation) is safe and leads to high survival rates in eligible patients with newly diagnosed PCNSL.

Gallop-Evans E
Primary central nervous system lymphoma.
Clin Oncol (R Coll Radiol). 2012; 24(5):329-38 [PubMed]

Primary central nervous system lymphoma is an aggressive lymphoma with a molecular biology and genetic profile that appears to be distinct from other types of diffuse large B-cell lymphoma. The median survival after whole brain radiotherapy alone is poor, but is significantly improved after high-dose methotrexate-based combination chemotherapy. The rarity of primary central nervous system lymphoma means that randomised studies have proved challenging, particularly as many patients are elderly and more susceptible to the toxic effects associated with these treatments. Promising treatment strategies are emerging and, wherever possible, patients should be treated within clinical trials. Quality of life and neurocognitive data should be collected prospectively to assess the effect of the disease and treatment.

Kasenda B, Rehberg M, Thürmann P, et al.
The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients.
Ann Hematol. 2012; 91(8):1257-64 [PubMed]

Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female N=30, male N=19, median age 73 years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [C (max), μmol/L g] and dose normalized area under the curve [AUC(dn), μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), P<0.001; 373.2 (f) vs. 271.9 (m), P=0.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126 h μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95 % CI 1.74-11.94; HR 2.87, 95 % CI 1.18-7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.

Okita Y, Narita Y, Miyakita Y, et al.
Long-term follow-up of vanishing tumors in the brain: how should a lesion mimicking primary CNS lymphoma be managed?
Clin Neurol Neurosurg. 2012; 114(9):1217-21 [PubMed]

OBJECTIVES: The spontaneous disappearance of a tumor is referred to as a vanishing tumor. Most vanishing tumors in the brain are eventually diagnosed as malignant tumors or multiple sclerosis. However, their long-term clinical course remains unclear. This study aims to elucidate the management of vanishing tumors in the brain.
PATIENTS AND METHODS: We defined a vanishing tumor as a case in which the tumor spontaneously disappeared or decreased to less than 70% of the initial tumor volume before definitive diagnosis and treatment (other than steroid treatment). Ten cases of vanishing tumors are reviewed.
RESULTS: Nine patients underwent biopsy at least once. Five patients, all of whom had malignant tumors (primary central nervous system lymphoma: 4, germinoma: 1) that recurred in 4-45 months (median: 7 months), underwent a second biopsy after the reappearance of the tumors. Five patients (tumefactive demyelinating lesion: 1, undiagnosed: 4) who had no relapse are alive, and their median follow-up time is 44 months. No cases have yet been reported of malignant brain tumors that recurred more than 5 years after spontaneous regression.
CONCLUSIONS: Patients with vanishing tumors should be followed up carefully by magnetic resonance imaging for at least 5 years, even after the disappearance of an enhancing lesion.

Ferreri AJ, Marturano E
Primary CNS lymphoma.
Best Pract Res Clin Haematol. 2012; 25(1):119-30 [PubMed]

Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumor with an unsatisfactory outcome. Therapeutic progress in this field is strongly conditioned by the limited biology and the molecular knowledge about this disease, which hamperizes the identification of new targeted therapies and the poor clinical conditions and performance status of patients, rendering very difficult their enrollment in prospective trials. Chemoradiation therapy is the most commonly used strategy for patients with PCNSL, which is associated with better efficacy rates, but also with high incidence of severe neurotoxicity. As a consequence, a dilemma in PCNSL treatment is the choice between strategies designed to intensify therapy to improve the cure rate, versus strategies of treatment de-escalation to avoid severe neurotoxicity. The efficacy of chemotherapy is strongly limited by the special functional and microenvironmental characteristics of the CNS, which is variably protected by the blood-brain barrier (BBB) and includes extensive chemotherapy sanctuaries where tumor cells grow undisturbed. Drugs exhibiting a good capability to cross the BBB and drugs that can be safely administered at high doses to obtain therapeutic concentrations in the CNS are the most commonly used in the treatment of PCNSL. Consolidation after chemotherapy represents the best role for radiotherapy. Since this tumor has an infiltrative nature, the whole brain should be irradiated, with increased risk of severe neurotoxicity. Some authorities are investigating in randomized trials the impact on outcome and neurotolerability of replacing consolidation radiotherapy with other strategies, like high dose chemotherapy supported by autologous stem cell transplantation. The rationale for the use of this strategy is the administration of high doses of cytostatics to achieve therapeutic concentrations in sanctuaries, CNS organs and lymphoma tissues and to overcome drug resistance mechanisms. Future therapeutic progresses in PCNSL will be based on the expansion of molecular and biological knowledge, the improvement of therapeutic efficacy and the prevention of iatrogenic neurotoxicity.

Korfel A, Weller M, Martus P, et al.
Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial.
Ann Oncol. 2012; 23(9):2374-80 [PubMed]

BACKGROUND: We evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial.
PATIENTS AND METHODS: MD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI).
RESULTS: Data on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MD-). There was a significant correlation of MD with CSF pleocytosis (>5/μl; P < 0.0001), but no correlation with CSF protein elevation (>45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0-14.5] in MD+ and 8.3 months (5.7-10.8) in MD- patients (P = 0.95); median overall survival was 21.5 months (95% CI 16.8-26.1) and 24.9 months (17.5-32.3), respectively (P = 0.98).
CONCLUSION: MD was detected infrequently and had no impact on outcome in this trial.

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