Is whole-brain irradiation necessary for primary central nervous system lymphoma? Patterns of recurrence after partial-brain irradiation

BACKGROUND: Neurotoxicity after whole-brain irradiation remains a major problem in the treatment of primary central nervous system lymphoma (PCNSL). To clarify whether whole-brain radiation is necessary for PCNSL, the authors retrospectively analyzed the outcome of patients treated with partial-brain irradiation. METHODS: A nationwide survey was performed regarding the treatment of PCNSL. Among 62 institutions surveyed, 7 were identified in which whole-brain irradiation was not necessarily employed. Questionnaires were sent to these institutions and 43 patients who had been treated using partial-brain fields since 1985 were collected. Thirty-two patients had solitary lesions and 11 had multiple lesions. Patterns of recurrence could be identified in 38 patients. RESULTS: The cumulative in-field and out-field recurrence rates at 5 years were 57% and 49%, respectively. Of 14 out-field recurrences, 2 occurred at the safety margin of the previous radiation field. The out-field recurrence rate was 45% in patients with a single lesion and 67% in those with multiple tumors (P = 0.79). The out-field recurrence rate was 22% for patients treated with safety margins of > or = 4 cm and 83% for those treated with safety margins of < 4 cm (P = 0.0079). The median survival time and the 5-year survival rate were 28.5 months and 20%, respectively, in the former group of patients and 15 months and 11%, respectively, in the latter group (P = 0.057). CONCLUSIONS: Focal radiotherapy with safety margins of < 4 cm appears to be associated with a very high rate of out-field recurrence, but the use of a radiation field with generous safety margins (> or = 4 cm) appears to be worth further investigation.     

Insights in primary central nervous system lymphoma: a role for glymphatics?

Brain Tumor Pathology -     

When do we need central nervous system prophylaxis in patients with extranodal NK/T-cell lymphoma,nasal type?

Background: The incidence and risk factors of central nervous system (CNS) invasion is still unclear in extranodal natural killer (NK)/T-cell lymphoma, nasal type.Patients and methods: We analyzed 208 patients to study the clinical features and outcomes of CNS disease in extranodal NK/T-cell lymphoma.Results: Twelve patients (5.76%, 12/208) experienced CNS disease during treatment or follow-up period (median 11.62 months, range 0.2–123.2 months). The clinical variables associated with CNS disease were Ann Arbor stage III/IV (15.87%, P <0.001), regional lymph node involvement (10.41%, P = 0.006), group III/IV of NK/T-cell lymphoma prognostic index (NKPI; 10.20%, P = 0.003), high/high–intermediate international prognostic index (9.30%, P = 0.072) and extra-upper aerodigestive primary sites (9.75%, P = 0.008). In multivariate analysis, NKPI retained the strongest statistical power to predict CNS disease (P = 0.007, relative risk 9.289, 95% confidence interval 1.828–47.212) in extranodal NK/T-cell lymphoma.Conclusions: Despite extranodal NK/T-cell lymphoma frequently involves paranasal sinus, a routine CNS evaluation and prophylaxis do not seem to be necessary in NKPI group I or II patients due to a very low incidence. Nevertheless, CNS prophylaxis should be considered in NKPI groups III and IV.     

Survival among patients with primary central nervous system lymphoma, 1973–2004

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin’s lymphoma that occurs in immunocompetent and human immunodeficiency virus (HIV) patients. Despite treatment advances, previous reports have produced conflicting information about survival trends over time. Using the Surveillance, Epidemiology, and End Results (SEER) data, 2,557 patients diagnosed with PCNSL between 1973 and 2004 were identified and classified by HIV status. Potential predictors of survival were evaluated using log-rank tests. Hazard ratios and 95% confidence intervals (CIs) were computed using a Cox proportional hazards regression model. The cohort included 1,732 (67.7%) HIV-negative patients and 825 (32.3%) HIV-positive patients. Median overall survival was 12 months (95% CI 10, 13) among HIV-negative patients. In this group, median survival increased over time, from 7.5 months (95% CI 6, 14) for patients diagnosed in the 1970s, to 14 months (95% CI 11, 20) for patients diagnosed in the 2000s. Independent predictors of mortality included older age (hazard ratio [HR] 1.03 [95% CI 1.02, 1.03]), earlier year of diagnosis (HR 0.98 [95% CI 0.98, 0.99]), male sex (HR 1.20 [95% CI 1.08, 1.34), married status (HR 0.70 [95% CI 0.63, 0.78]), and receipt of radiation therapy (HR 0.69 [95% CI 0.61, 0.77]). HIV positivity was a powerful adverse prognostic factor in the overall cohort (HR 4.55 [95% CI 4.01, 5.16]). Despite treatment advances, survival among PCNSL patients in the United States remains poor. However, in the subset of PCNSL patients who are HIV-negative, survival has improved over time.     

Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? The University of Rochester experience

Various subsets of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) have been associated with infectious organisms. Most notable of these is the association of gastric MALT lymphomas with Helicobacter pylori infection. In a recent publication Ferreri et al. [Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell'Oro S, Fleischhauer K, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004;96:586-94] reported the presence of C. psittaci DNA in 80% of 40 ocular adnexal lymphomas. Similar to the gastric MALT lymphoma data, a subset of these patients responded well to antibiotic treatment. We analyzed a set of ocular adnexal lymphomas and benign (non-neoplastic) lesions for evidence of C. psittaci DNA in patients from New York State. No evidence of C. psittaci DNA was seen in seven MALT-type ocular adnexal lymphomas, four non-MALT ocular lymphomas, one Langerhans histiocytosis, and five reactive lymphoproliferations. We eliminated several possible reasons that would cause our study to fail to find C. psittaci DNA, including the presence of PCR inhibitors, inadequate template DNA, and sequence diversity in the target region in C. psittaci. The positive data were based primarily on patients from Italy, while our study involved only patients living in the Northeastern United States. This would suggest possible geographic differences in the etiology of ocular adnexal lymphomas.     

Primary central nervous system lymphoma: is absence of intratumoral hemorrhage a characteristic finding on MRI?

Background.

Previous studies have shown that intratumoral hemorrhage is a common finding in glioblastoma multi-forme, but is rarely observed in primary central nervous system lymphoma. Our aim was to reevaluate whether intratumoral hemorrhage observed on T2-weighted imaging (T2WI) as gross intratumoral hemorrhage and on susceptibility-weighted imaging as intratumoral susceptibility signal can differentiate primary central nervous system lymphoma from glioblastoma multiforme.

Patients and methods.

A retrospective cohort of brain tumors from August 2008 to March 2013 was searched, and 58 patients (19 with primary central nervous system lymphoma, 39 with glioblastoma multiforme) satisfied the inclusion criteria. Absence of gross intratumoral hemorrhage was examined on T2WI, and an intratumoral susceptibility signal was graded using a 3-point scale on susceptibility-weighted imaging. Results were compared between primary central nervous system lymphoma and glioblastoma multiforme, and values of P < 0.05 were considered significant.

Results.

Gross intratumoral hemorrhage on T2WI was absent in 15 patients (79%) with primary central nervous system lymphoma and 23 patients (59%) with glioblastoma multiforme. Absence of gross intratumoral hemorrhage could not differentiate between the two disorders (P = 0.20). However, intratumoral susceptibility signal grade 1 or 2 was diagnostic of primary central nervous system lymphoma with 78.9% sensitivity and 66.7% specificity (P < 0.001), irrespective of gross intratumoral hemorrhage.

Conclusions.

Low intratumoral susceptibility signal grades can differentiate primary central nervous system lymphoma from glioblastoma multiforme. However, specificity in this study was relatively low, and primary central nervous system lymphoma cannot be excluded based solely on the presence of an intratumoral susceptibility signal.     

Is mortality due to primary malignant brain and other central nervous system tumors decreasing?

Primary malignant brain and other central nervous system tumors (BT) are a rare cancer that causes morbidity and mortality disproportionate to their incidence. This study presents the most up-to-date mortality data for malignant BT in the United States (US) by histology groupings, age, race, and sex. Mortality rates for malignant BT were generated using the Center for Disease Control’s National Vital Statistics Systems (NVSS, ~100% of US) data from 1975 to 2012. Histology-specific incidence-based mortality rates were calculated using the National Cancer Institute’s Surveillance, Epidemiology, and End-Results 9 (SEER9, ~9.4% of US) data from 1975 to 2012. Joinpoint modeling was used to estimate trends. Mortality was similar in both the NVSS and SEER9 datasets. Overall, mortality from 1975 to 2012 was higher among men, higher in older individuals, and higher in Whites compared to other races. Persons age 65+ years had significant increases in mortality for all malignant tumors overall and for glioma histologies, while persons age <20 years had no significant changes in mortality. This study reports up-to-date mortality rates by histology groupings, age, race, and sex for malignant BT. There have been no significant changes in overall mortality due to these tumors from 1975 to 2012. There have been significant increases in mortality in the elderly (age 65+ years), especially those age 75–84 years, mirroring the effect of overall population aging. Examining age-, race-, sex-, and histology-specific morality at the population level can provide important information for clinicians, researchers, and public health planning.     

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma： Case report and literature review

Objective  

The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.     

Survival from tumours of the central nervous system in Danish children: Is survival related to family circumstances?

Little is known about social inequalities in childhood cancer survival. We investigated the impact of family circumstances on survival from paediatric central nervous system (CNS) tumours in a nationwide, register‐based cohort of Danish children. All children born between 1973 and 2006 and diagnosed with a CNS tumour before the age of 20 years (N = 1,261) were followed until 10 years from diagnosis. Using Cox proportional hazards models, the impact of various family characteristics on overall survival was estimated. Hazard ratios (HRs) for all CNS tumours combined did not show strong associations between survival and any family characteristic. Analyses by CNS tumour subtypes showed reduced survival for children with glioma when living outside of Copenhagen (HR 1.55; CI 1.03; 2.35). For embryonal CNS tumours, the number of full siblings was associated with worse survival (HR for having 3+ siblings 3.60; CI 1.52; 8.53) and a trend of better survival was observed for children with parents of younger age at child's diagnosis and poorer survival of children with parents of older age. Despite free and uniform access to health care services, some family circumstances appear to affect survival from specific CNS tumour types in Danish children. Further research is warranted to gain a more comprehensive understanding of the impact of family factors on childhood cancer survival in other populations and to elaborate underlying mechanisms and pathways of those survival inequalities observed.     

Complete response to therapy: why do primary central nervous system lymphoma patients not return to work?

Journal of Neuro-Oncology - Evidence supporting routine postoperative antiepileptic drug (AED) prophylaxis following oncologic neurosurgery is limited, and actual practice patterns are largely...     

Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor α in primary central nervous system lymphoma

Purpose Primary central nervous system lymphomas (PCNSL) are rare tumours occurring in the brain. Their biology and the factors predicting survival are not well known. This study investigated expression of the antiapoptotic protein survivin and platelet-derived growth factor A (PDGF-A) and receptor (PDGFRα) in PCNSL.Experimental design A total of 44 patients with histologically confirmed PCNSL treated between 1992 and 2004 were included in this study, and tumour specimens were investigated immunohistochemically for expression of survivin, PDGF-A and PDGFRα. Protein expression and clinical variables were analyzed statistically.Results Of the 44 tumours 43(98%) were diffuse large B-cell non-Hodgkin’s lymphomas (NHL) and one was a T-cell NHL. Around 37 (84%) of the examined PCNSL specimens showed expression of survivin, 16 (36%) of PDGF-A and 34 (77%) of PDGFRα. Tumours expressing surviving co-expressed PDGFRα frequently and PDGF-A occasionally. Expression of the above proteins was not predictive for survival in this patient group. Except for age and therapy, no other clinical variables correlated significantly with overall survival.Conclusions PCNSL express survivin and PDGFRα in the majority of investigated cases. PDGF-A is expressed less frequently. Immunohistochemical detection of these proteins does not correlate with overall survival and cannot be used as a prognostic factor.These authors have contributed equally to the study     

Consolidation regimens in primary central nervous system lymphoma: a single-center retrospective cohort evaluating survival outcomes and cost–benefit analysis

Journal of Neuro-Oncology - Optimal treatment for primary central nervous system lymphoma (PCNSL) comprises polychemotherapy induction with high-dose methotrexate followed by consolidation therapy,...     

Prevention of radiation-induced central nervous system toxicity: a role for amifostine?

PURPOSE: To review the role of amifostine (WR-2721) in ameliorating radiation-induced central nervous system (CNS) toxicity. MATERIALS AND METHODS: Literature review and presentation of preliminary animal experiments designed to test the efficacy of both intrathecal and subcutaneous application of amifostine. RESULTS: Despite its inability to cross the blood-brain barrier, amifostine appears promising because it protects blood vessels against radiation-induced damage. Vascular damage is one of the most important components in the development of CNS toxicity after radiotherapy. Furthermore, the increased permeability of the blood-brain barrier during fractionated radiotherapy might allow penetration of amifostine. Three animal studies with systemic administration found positive results after brain irradiation with different fractionation schedules, total doses and amifostine doses. One study where amifostine was given after radiotherapy showed no protection, suggesting that the timing of the drug application is crucial. Further data suggest that either intrathecal or systemic administration might protect the spinal cord as well. In our experience with spinal cord irradiation, systemic administration was more effective than intrathecal. Regarding CNS protection, the optimum dose of amifostine has yet to be determined. CONCLUSION: Several independent experiments provided preliminary evidence that modulation of the radiation response of the CNS in vivo by systemic administration of amifostine is possible and feasible. Additional studies are warranted to investigate the protective effect with differing regimens of administration, more clinically relevant fractionation regimens and longer follow-up.     

Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?

In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy.