Combined modality therapy for primary CNS lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL. PATIENTS AND METHODS: Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991. RESULTS: Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival. CONCLUSION: The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.     

盖诺加顺铂联合放疗同步治疗局部晚期非小细胞肺癌的临床研究

目的评价去甲长春花碱（NVB,商品名盖诺）加顺铂（DDP）联合放疗同步治疗局部晚期非小细胞肺癌（NSCLC）的临床疗效和不良反应。方法64例局部晚期NSCLC患者完全随机分为联合组（33例）和化疗组（31例）。化疗组单纯采用NP方案化疗,其中NVB25mg／m^2,d1,8;DDP25-30mg/m^2,d1—d3。联合组在NP方案化疗基础上,同时进行常规放疗。结果64例患者全部完成治疗计划,联合组总有效率（81．8％）明显高于化疗组（45．2％,P〈0．05）;联合组的1,2年生存率分别为69．7％和39．4％,化疗组分别为38．7％和16．1％,差异有统计学意义（P〈0．05）。联合组不良反应稍高于化疗组,但差异无统计学意义（P〉0．05）。结论盖诺加顺铂联合放疗同步治疗局部晚期NSCIE有较好的近期疗效,可提高生存率,毒性反应可耐受。     

Secondary acute myeloid leukemia with inv(16): report of two cases following paclitaxel-containing chemotherapy and review of the role of intensified ara-C therapy.

Acute myeloid leukemia developing secondary to prior cytotoxic chemotherapy (s-AML) encompasses a range of distinct entities. We report two cases of s-AML with inv(16)(p13q22) who had prior exposure to paclitaxel. Additionally, two previously reported cases of s-AML with inv(16) had prior paclitaxel exposure raising the possibility that the taxanes may predispose to this specific syndrome of s-AML. One of our patients received escalated-dose ara-C chemotherapy, achieving a complete remission (12+ months). We therefore examined the prognosis of previously reported cases of s-AML with inv(16) and analyzed the influence of escalated-dose ara-C (>/=400 mg/m2/day). A total of 25 evaluable cases were identified, with 96% attaining CR independent of ara-C dose. The estimated median remission duration was 40 months and the median survival has not been reached (actuarial 5-year survival 52 +/- 18%). Although not achieving statistical significance, patients treated with escalated dose ara-C (n = 15) had longer remission duration and overall survival than those treated with standard dose ara-C (n = 10) (P = 0.063 and 0.20, respectively). In univariate analysis, younger age, male gender, and the presence of additional cytogenetic abnormalities were associated with a tendency towards adverse outcomes (P< 0.1). Age and gender were equally distributed between ara-C dose cohorts, but more patients treated with standard-dose ara-C had additional cytogenetic abnormalities (P = 0.048). Within the limitations of this retrospective study, this analysis suggests that, similar to de novo AML with inv(16), secondary cases may also potentially benefit from treatment with escalated-dose ara-C. This is consistent with the premise that the underlying molecular defect, rather than the presence of prior cytotoxic drug exposure, may be the most important determinant of disease behavior and chemotherapy responsiveness in AML.     

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma

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.     

Leptomeningeal metastases due to melanoma

A Phase II study of combined modality therapy of leptomeningeal metastases (LM) in melanoma was carried out. Central nervous system (CNS) metastases occur commonly in patients with clinically advanced melanoma. 16 patients (median age 47; range 32-62 years) with LM due to metastatic melanoma were treated. Neurologic presentation included: headache (9 patients); cranial neuropathies (6); cauda equina syndrome (4); gait ataxia (3); hemiparesis (2); radiculopathy (2); myelopathy (1); and seizure (1). All patients underwent CNS staging followed by radiotherapy (14 patients) and intraventricular chemotherapy (methotrexate 16 patients; ara-C 13 patients; thio-TEPA 7 patients). CNS imaging demonstrated: interrupted CSF flow (9 patients); parenchymal brain metastases (7); spinal cord subarachnoid nodules (5); hydrocephalus (3); and epidural spinal cord compression (2). CSF cytologic responses were seen in 4 patients to first-, 6 to second-, and 3 to third-line chemotherapy. Treatment-related toxicity included 13 patients with meningitis (12 chemical; 1 bacterial) and 12 patients (18 episodes) with myelosupression (4 episodes secondary to intraventricular chemotherapy). Median survival was 4 months (range: 2-8). Twelve patients (75%) died of progressive LM or combined LM and systemic disease progression. LM in patients with metastatic melanoma may be palliated with combined modality therapy, however, median survival is quite short suggesting a re-evaluation of such an approach in similarly affected patients.     

75例原发中枢神经系统淋巴瘤临床分析

  目的  探讨原发中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）的临床特征、治疗方案及预后相关因素。  方法  回顾性分析2011年11月至2015年11月郑州大学第一附属医院收治的75例免疫功能正常的PCNSL患者临床资料。采用K-M法及Cox多因素回归模型进行生存资料分析。  结果  75例PCNSL患者中位发病年龄为55（9~79）岁,男女比为1.1:1。颅内压增高及局灶性神经系统损害为主要表现。病理类型均为弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）。随访到69例,其中术后放化疗联合组25例、术后化疗组28例、术后放疗组9例及单纯手术治疗组7例。中位无进展生存期（median overall progression-free survival,mPFS）分别为23.6（95%CI:16.0~31.3）、6.4（1.0~11.8）、9.8（4.7~14.9）和5.0（4.9~5.2）个月,中位总生存期（median overall survival,mOS）分别为45.7（95%CI:44.2~47.2）、11.0（7.1~15.0）、16.1（15.3~17.0）和6.9（1.9~12.0）个月,差异均具有统计学意义（P < 0.01）。单因素及多因素分析均表明发病年龄及东部肿瘤协作组体力状况评分（ECOG）与生存期相关。  结论  :PCNSL多发于中老年人,类型以DLBCL多见,临床表现以颅内压增高和局灶性神经系统损害为主。年龄≤60岁、ECOG评分≤1分的患者预后较好。术后行放化疗治疗可显著提高患者生存期。      

Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy.

PURPOSE: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.     

Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10.

PURPOSE: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We prospectively studied the use of combination chemotherapy plus cranial irradiation in newly diagnosed patients with PCNSL. PATIENTS AND METHODS: We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98 were assessable. Patients first received five cycles of methotrexate 2.5 g/m(2), vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain radiotherapy (RT) was administered to a total dose of 45 Gy and all patients received high-dose cytarabine after RT. RESULTS: Fifty-eight percent of patients with measurable disease had a complete response to preirradiation chemotherapy and 36% had a partial (> 50%) response, for a 94% response rate. Median progression-free survival was 24.0 months and overall survival was 36.9 months. Age was an important prognostic factor; median survival was 50.4 months in patients younger than 60 and only 21.8 months in those aged 60 or older (P <.001). Fifty-three percent of patients had grade 3 or 4 toxicity during induction chemotherapy, half of which was hematologic. However, 12 patients (15%) experienced severe delayed neurologic toxicity, eight of whom died. CONCLUSION: This is the first multicenter trial demonstrating improved survival with the combination of chemotherapy plus RT compared with previous reports of RT alone. A high-dose methotrexate-based regimen produced a high response rate before RT was administered. High-dose methotrexate combined with cranial irradiation is an effective therapeutic approach to PCNSL, but neurotoxicity is a delayed risk of this approach.     

Lymphomatous meningitis in immunocompetent patients

A prospective study of combined modality therapy of non-AIDS related lymphomatous meningitis was carried out. Lymphomatous meningitis is diagnosed increasingly as anti-lymphoma therapies become more effective and result in prolonged patient survival. Twenty-two patients (range 38-69 years; median 60) with lymphomatous meningitis due to metastatic non-AIDS related non-Hodgkins lymphoma were treated. Neurologic presentation included: headache (n=13); cranial neuropathies (n=9); ataxia (n=5); cauda equina syndrome (n=3); myelopathy (n=1); and meningismus (n=1). All patients underwent radiographic evaluation of the extent of central nervous system disease (CNS) followed by radiotherapy (n=8) and sequential intraventricular chemotherapy (methotrexate in 22 patients; cytarabine in 12; thio-TEPA in 5). CNS imaging demonstrated: interrupted CSF now (n=8); intra-cranial subarachnoid nodules (n=2); hydrocephalus (n=2); spinal subarachnoid nodules (2); nerve root enhancement (n=2); and epidural spinal cord compression (n=1). Cytologic responses were seen in 16 patients (73%) to first-, 7 (58%) to second- and 2 (40%) to third-line chemotherapy. Treatment-related toxicity included 14 patients (64%) with aseptic meningitis and 12 patients (55%) with thrombocytopenia or neutropenia (all unrelated to intraventricular chemotherapy). Median survival was 10 months (range: 3-24 months). Fourteen patients (64%) died of their systemic disease, 3 patients (14%) died of progressive lymphomatous meningitis, 4 patients (19%) died of progressive combined systemic disease in lymphomatous meningitis and 1 patient (5%) is disease-free. Fourteen patients (64%) received concurrent systemic chemotherapy and no differences were seen in outcome within this group of patients including 6 patients treated with dose intensive chemotherapy and autologous bone marrow transplantation. Lymphomatous meningitis in patients with non-AIDS related non-Hodgkin's lymphoma may be palliated with combined modality therapy, however, despite the application of standard or dose intensive systemic chemotherapy, therapy remains non-curative.     

Induction cisplatin-gemcitabine-paclitaxel plus concurrent radiotherapy and gemcitabine in the multimodality treatment of unresectable stage IIIB non-small cell lung cancer

BACKGROUND: To evaluate feasibility and safety of induction three-drugs combination chemotherapy and concurrent radio-chemotherapy in stage IIIB NSCLC. PATIENTS AND METHODS: Patients with stage IIIB NSCLC were treated with three courses of induction chemotherapy, cisplatin 50 mg/m(2), paclitaxel 125 mg/m(2) and gemcitabine 1000 mg/m(2) on days 1,8 of every 21 day cycle. Patients without distant progressive disease were then treated with radiotherapy and concurrent weekly gemcitabine (250 mg/m(2)). Toxicity and response of radio-chemotherapy treatment have been assessed. RESULTS: Between Jan 01 and Nov 02, 46 patients were enrolled. Grade 3+ hematological and non-hematological toxicity during the induction phase were 41.3% and 13.1%, respectively. In 38 patients a Clinical Response or Stable Disease was recorded and these patients underwent to concurrent radio-chemotherapy. Grade 3+ hematological and non-hematological toxicities were 8.2% in this group. Further response was observed in 66% of patients. Overall median survival time was 17.8 months, with a 3-year survival rates of 23%. CONCLUSION: Three-drugs induction chemotherapy and concurrent radio-chemotherapy with weekly gemcitabine in locally advanced stage IIIB NSCLC is feasible and safe.     

Primary central nervous system lymphomas: incidence and survival in the Southern and Eastern Netherlands

BACKGROUND: An excessive increase in the incidence of primary central nervous system lymphoma (PCNSL) has been reported since the mid-1980s in the U.S. and U.K. Clinical studies have shown that radiotherapy and chemotherapy may prolong survival. In the current study, the authors describe the incidence, treatment, and survival of an unselected group of patients with PCNSL in the southern and eastern Netherlands. METHODS: Data regarding patients diagnosed between 1989-1994 were obtained from 4 population-based regional cancer registries in the southern and eastern Netherlands (n = 86) and the Eindhoven Cancer Registry for 1980-1988 (n = 6). Lymphomas were registered as PCNSL when a tissue diagnosis of CNS lymphoma was established for a patient with neurologic symptoms (i.e., lymphomas were not necessarily restricted to the CNS at the time of diagnosis). Only patients diagnosed during their lifetime with Stage I disease, Stage "IV" disease (i.e., diffuse CNS lymphoma), or disease of unknown stage were included (63 patients, 8 patients, and 15 patients, respectively, between 1989-1994). For 80 patients (93%) follow-up was complete until January 1, 1997. RESULTS: Between 1989-1994, an average World Standardized Rate of 2.3 cases and 1.7 cases per 1 million person-years, respectively, was reported for males and females. The median age of the patients at the time of diagnosis was 62 years, and was 66 years for patients with an unknown disease stage. In the area of the Eindhoven Cancer Registry the occurrence of PCNSL more than doubled from < 2% of all histologically confirmed primary CNS malignancies diagnosed between 1980-1985 to approximately 4% of cases diagnosed between 1986-1994. The median survival of all the patients was 4.1 months; the median survival was 5.8 months for patients with limited (Stage I and Stage IV) disease and was 0.6 months for patients with an unknown stage of disease. Approximately 65% of the patients with limited disease received radiotherapy and approximately 35% of such patients received chemotherapy. Furthermore, chemotherapy was given more often to patients age < 60 years who tended to have a slightly better survival than patients age > or = 60 years. CONCLUSIONS: The increase in the incidence of PCNSL in the 1980s may be explained in large part by changes in diagnostics and registration. The relatively high incidence and low survival rate of PCNSL in the southern and eastern Netherlands reported in the 1990s may be due in part to the inclusion of patients with systemic lymphoma and immunodeficiency disorders. However, a significant improvement in the prognosis of patients with PCNSL in the southern and eastern Netherlands diagnosed in the 1990s is unlikely.     

Pemetrexed for primary central nervous system lymphoma in the elderly

Objective

The aim of this study was to evaluate the efficacy and safety of a consecutive series of elderly patients with primary central nervous system lymphoma (PCNSL) treated with single-agent pemetrexed without radiotherapy or intrathecal chemotherapy.

Methods

Twelve histologically confirmed newly diagnosed PCNSL patients older than 65 years were studied between 2008 and 2013. An induction chemotherapy was initially given (pemetrexed 600 mg/m² on day 1, every 3 weeks). Patients achieving a complete, partial response or stable disease proceeded to a maintenance phase (up to 6 cycles). Patients with progressive/recurrent disease (PD) were treated with whole brain radiotherapy on an individual basis.

Results

Four patients presented complete response, six patients showed partial response and two patients presented progressive disease. The median progression-free survival (PFS) was 9.0 months [95 % confidence interval (CI) 2.0–45.3] and the median overall survival was 19.5 months (95 % CI 5.0–45.3). Adverse events included leukocytopenia, anemia, fatigue, rash and vomiting. No neurotoxicity or treatment-related death was observed. The estimated 1-year and 2-year survival rate was 66.7 and 41.7 %, respectively.

Conclusions

Our efficacy results demonstrate that the single-agent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this single-agent regimen results in higher response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. Prospectively, controlled studies are warranted to confirm such results.

     

Primary central nervous system lymphoma: a clinicopathological study of 28 cases

A group of 28 consecutive patients (mean age 59 years) with primary central nervous system lymphoma (PCNSL) was treated with different regimens, including steroids only, radiotherapy (RT), chemotherapy or combinations of all. Lymphoma was classified as high grade malignant B-cell non-Hodgkin's lymphoma of the diffuse large cell type in each of these cases. RT alone led to tumour remission in more than 70 per cent, survival could be prolonged with additional chemotherapy. Thirteen patients were treated with chemotherapy alone; nine of them received a novel combined intraventricular and systemic polychemotherapy protocol based on high dose methotrexate (MTX) and high dose cytarabine (ara-C). The response rate was 90 per cent with 80 per cent complete responses. Neurotoxicity, i.e. white matter lesions associated with severe cognitive dysfunction affected both patients surviving RT more than a year and patients treated with combination RT/chemotherapy. Confluent white matter hyperintense lesions were detectable on MRI in three out of 13 patients treated with chemotherapy alone, however, cognitive dysfunction has not been detected in these patients.     

Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study

Background A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. Patients and methods From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. Conclusions In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment. H. Pels and A. Juergens contributed equally.     

Current status and future of relapsed primary central nervous system lymphoma (PCNSL)

The treatment of primary central nervous system lymphoma (PCNSL) has centered around high-dose methotrexate and radiotherapy (RT). Methotrexate administered intra-arterially (IA) with blood-brain barrier disruption (BBBD) and without RT, has been a highly effective treatment with a 5 year survival of 42% without cognitive loss. The purpose of this analysis is to determine responses for patients with relapsed PCNSL treated with second line IA carboplatin-based chemotherapy with BBBD. Between February 1991 and April 2000, 37 relapsed PCNSL patients, most who failed front line therapy with methotrexate based chemotherapy, were treated at Oregon Health & Science University (OHSU) and Hadassah Hebrew University Hospital (HHUH) with IA carboplatin-based chemotherapy with BBBD. Nine patients had prior RT. The mean age was 57.5 years, and all but 1 patient were treated within 8 months after relapse. The median time for survival from first IA carboplatin/BBBD treatment was 6.8 months;however, 7 out of 37 patients survived > or = 27 months. Nine patients had radiographic complete response (CR), 4 patients had radiographic partial response (PR), 12 had stable disease (SD), 10 had progressive disease (PD), and 2 were non-evaluable. The median time to failure for patients with CR and PR was 9.1 months. One long-term survivor is alive at 91.0 months from first carboplatin/BBBD treatment. In conclusion, we show that relapsed PCNSL has shown sensitivity to second line IA carboplatin-based chemotherapy with BBBD. We have developed a new protocol using i.v. rituximab prior to BBBD with IA carboplatin, i.v. cyclophosphamide and i.v. etoposide phosphate. The long-term program goal is to consolidate dose-intensive chemotherapy with monoclonal antibody directed radiation. Because patients with recurrent PCNSL commonly continue to relapse even after obtaining a complete response to enhanced chemotherapy treatment, patients w ho complete or fail the above carboplatin/BBBD treatment regimen will be offered consolidation with radioimmunotherapy using zevalin (Ibritumomab tiuxetan), IDEC-2B8 conjugated with yttrium-90 (90Y).     

The treatment of primary central nervous system lymphoma in 122 immunocompetent patients: a population-based study of successively treated cohorts from the British Colombia Cancer Agency

BACKGROUND: The objective of this study was to evaluate the clinical outcome of a population-based cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) treated with 3 different strategies over 13 years. METHODS: One hundred twenty-two consecutive patients (median age, 66 years) with PCNSL were identified. Three treatment strategies were employed: 1) whole-brain irradiation with (from January, 1990, to June, 1991) or without (from April, 1995, to December, 1999) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-type chemotherapy (n=50 patients); 2) combined-modality therapy, including 1 g/m2 methotrexate plus whole-brain irradiation (from July, 1991, to March, 1995; n=34 patients); and 3) 8 g/m2 methotrexate alone (from January, 2000, to March, 2003) with whole-brain irradiation reserved for those with progressive disease (n=38 patients). Treatment failure was defined as progressive disease, disease recurrence, death from toxicity or lymphoma, or toxicity that necessitated a change in primary treatment. RESULTS: The median failure-free survival was 7 months, and the median overall survival (OS) was 17 months. The median OS was similar in all 3 eras. In this population-based analysis, one-third of patients did not receive the treatment strategy of the era. Therefore, the data also were analyzed by treatment received. On multivariate analysis (including era of treatment), 3 factors-age > 60 years, lactate dehydrogenase > normal, and omission of methotrexate-were associated significantly with poorer OS (hazard ratio: 2.3, 2.2, and 2.3, respectively). CONCLUSIONS: Outcomes for a general population with PCNSL remained constant despite different treatment strategies over three eras. For the two-thirds of patients who could receive potentially curative treatment, age, lactate dehydrogenase level, and receipt of > or = 1 g/m2 methotrexate appeared to be important determinants of OS.     

Treatment outcomes and survival in patients with primary central nervous system lymphomas treated between 1995 and 2010 – a single centre report

Background.

Primary central nervous system lymphomas (PCNSL) are rare variants of extranodal non-Hodgkin’s lymphomas that are nowadays primarily treated with high-dose methotrexate or methotrexate-based chemotherapy with or without radiation therapy. The optimal treatment of PCNSL is still unknown and there are differences in clinical practice.

Patients and methods.

With a retrospective research we evaluated our series of patients with PCNSL in regards to the patient’s characteristics, treatment results, disease specific survival and overall survival. Fifty nine patients who attended the Institute of Oncology Ljubljana between 1995 and 2010 were treated according to the protocol that was valid at the time of the patient’s admission. Between 1995 and 1999, the systemic treatment was classical CHOP (cyclophosphamide, doxorubicin, vincristine, steroids) chemotherapy, and later on high-dose methotrexate either alone or in combination with other agents. From 1999 onwards, radiation therapy was applied according to the patient’s age and response to chemotherapy, prior to that all patients treated with CHOP were also irradiated. Patients ineligible for the systemic treatment were treated with sole radiation therapy.

Results.

There was a strong female predominance in our series and the median age at diagnosis was 59.8 years. Patients had predominantly aggressive B cell lymphomas (69.5%), one patient had marginal cell lymphoma and two patients T cell lymphoma. In total, 20.3% of patients were treated just with chemotherapy, 33.9% with combined therapy and 42.4% with sole radiation therapy. The overall response rate to the primary treatment in patients treated with sole chemotherapy was 33.3%, in patients treated with combined therapy 65% and in patients treated only with radiation therapy 56%, respectively. In terms of response duration, significantly better results were achieved with combined therapy or radiation therapy alone compared to sole chemotherapy (p<0.0006). The median overall survival of the whole cohort was 11 months and the overall survival was significantly affected by the patient’s age. The longest overall survival was observed in patients treated with combined therapy (median survival of 39 months). Patients treated just with radiation therapy had a median overall survival of 9 months and those treated with sole chemotherapy of 4.5 months, respectively.

Conclusions.

The treatment outcomes in ordinary clinical practice are definitely inferior to the ones reported in clinical trials. The now standard treatment with high-dose methotrexate with or without radiation therapy is sometimes too aggressive and, therefore, a careful selection on the basis of patient’s age, performance status and concomitant diseases of those eligible for such treatment is mandatory. According to our results from a retrospective study, radiation therapy should not be excluded from the primary treatment.     

Prolonged Response and Restoration of Functional Independence with Bevacizumab plus Vinorelbine as Third-Line Treatment for Breast Cancer-Related Leptomeningeal Metastases

Background

Survival of patients with leptomeningeal metastases (LM) and impaired functional status is limited to several months, and rarely does neurological function improve with treatment.

Case Report

A 34-year-old female with hormone-negative and HER2-positive metastatic breast cancer was diagnosed with bulky radiographic LM 45 months after initial diagnosis. She was treated with intra-CSF trastuzumab followed by intra-CSF liposomal cytarabine; however, the cancer progressed 8 months after the diagnosis of LM. At the time of the third LM progression, the patient presented with a cauda equina syndrome and cerebellar impairment resulting in an inability to walk. She was treated with CNS-directed radiotherapy (lumbosacral and cerebellar) and bevacizumab plus vinorelbine. Rapid functional improvement occurred, and the patient regained the ability to walk and independently manage her daily activities. Twelve months later, she presented with rapid progression of the LM resulting in death within several weeks.

Conclusion

In radiographically defined bulky LM, the combination of systemic therapy and CNS-directed radiotherapy likely is more active than intra-CSF therapy only. In lieu of the rapid and significant improvement in neurological function combined with the prolonged response, bevacizumab alone or in combination with chemotherapy and CNS-directed radiotherapy may be considered in select patients with radiographically bulky breast cancer-related LM.Key Words: Leptomeningeal metastases, Neoplastic meningitis, Breast cancer, Bevacizumab, Quality of life, Symptom control     

31例原发性中枢神经系统恶性淋巴瘤临床分析

目的:分析免疫正常的原发性中枢神经系统恶性淋巴瘤患者的临床表现、影像学特点和病理表现并探讨其诊断、治疗方法。方法:回顾分析1995年7月至2006年6月经过病理证实的31例原发中枢神经系统恶性淋巴瘤病例的l临床、实验室检查、影像学、病理结果及治疗效果。18例采用手术 放疗 化疗方法,5例单纯手术治疗。其中化疗CHOP方案11例,替尼泊苷(VM26) 司莫司汀(me-CCNU)7例。结果:原发性中枢神经系统恶性淋巴瘤临床表现复杂,无特异性,主要为颅内压增高和神经功能缺损为主,误诊率高。脑脊液检查无阳性结果。31例均为B细胞淋巴瘤。31例中获随访24例,随访时间6～98个月,其中手术 放疗 化疗组中位生存期20个月,单纯手术组中位生存期10个月。应采取综合治疗。结论:原发性中枢系统恶性淋巴瘤缺乏特异性临床表现,术前难以确诊,预后不良。病理检查是确诊的唯一方法。手术的主要目的是解除肿瘤引起的颅内高压,单纯手术后,短时间内复发,应该采取手术、放疗、化疗综合治疗,这是延长生存期和改善生存质量的关键。     

非免疫缺陷原发性中枢神经系统淋巴瘤17例临床分析(英文)

Objective: The aim of this study was to investigate the clinical manifestations of primary central nervous system lymphoma (PCNSL) with non-immune deficiency and explore effective methods for its diagnosis and treatment. Methods: The clinical, imaging and pathological data from 17 cases with PCNSL in our hospital from March 2006 to April 2009 were analyzed. The immunologic function test for all 17 cases was confirmed as normal. Four of them received stereotactie brain biopsy while the other patients were given full or partial resection. Fifteen of them were given both radiotherapy and chemotherapy after surgery. High-dose Methotrexate (HD-MTX) (2.0g/m2) was used via intravenous infusion once per week for three times. From week 4, patients began radiotherapy. Six cases with abnormal cerebrospinal fluid were given whole central nervous system radiotherapy, and 9 cases with normal cerebrospinal fluid were given only whole brain radiotherapy. Two of them were without any additional treatment after surgery. Sixteen of 17 cases were followed up for 9-48 months. Therapeutic efficacy, toxic and side effect were investigated. Results: Six cases, who were given HD-MTX chemotherapy and whole central nervous system radiotherapy, had grade 3 leukopenia, but other toxic and side effect above grade 3 were not observed. Two patients having no chemotherapy and radiotherapy recurred in one month, but there was only one recurred case in three months among 15 cases who had both chemotherapy and radiotherapy. One of them lost fellow-up. The 2-year survival rate was 69.2%. Conclusion: There is no specific clinical manifestation for PCNSL. The pathological examination is a reliable method to confirm PCNSL. Recurrence may occur after surgery alone, however, the combination of HD-MTX chemotherapy and radiotherapy is an effective and safe therapeutic option, which might improve the treatment efficiency and survival rate.