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1.
Chirurg ; 93(3): 274-285, 2022 Mar.
Article in German | MEDLINE | ID: mdl-34374822

ABSTRACT

Analysis of the quality of care for colorectal cancer is an essential foundation for further development and is based on the comparison of the goals set and the actual quality of care. This publication presents the reality of care in the State of Brandenburg covering the complete spectrum of treating clinics based on the data of the clinical cancer register. This study analyzed the number of resected and examined lymph nodes, the quality of total mesorectal excision (TME), the residual tumor (R0) resection rate and the proportion of adjuvant therapy of colon cancer in Union internationale contre le cancer (UICC) stage III depending on the operation quota of hospitals and the certification as bowel cancer center according to Onkozert. Apart from the R status, the analyses showed no differences in the qualitative operation data from the clinical cancer register depending on the hospital volume.


Subject(s)
Rectal Neoplasms , Certification , Hospitals , Humans , Lymph Node Excision , Lymph Nodes/pathology , Neoplasm Staging , Rectal Neoplasms/surgery , Retrospective Studies
2.
Neurology ; 84(12): 1242-8, 2015 Mar 24.
Article in English | MEDLINE | ID: mdl-25716362

ABSTRACT

OBJECTIVE: This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months. METHODS: Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)-based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9. RESULTS: In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio [HR] 0.83 [95% confidence interval (CI) 0.65-1.06], p = 0.14) and significantly PFS from last HDMTX (25.5 vs 12.0 months, HR 0.65 [95% CI 0.5-0.83], p = 0.001), but without OS prolongation (35.6 vs 37.1 months, HR 1.03 [95% CI 0.79-1.35], p = 0.82). In the intent-to-treat population (n = 410), there was a prolongation by WBRT of both PFS (15.4 vs 9.9 months, HR 0.79 [95% CI 0.64-0.98], p = 0.034) and PFS from last HDMTX (19.4 vs 11.9 months, HR 0.72 [95% CI 0.58-0.89], p = 0.003), but not of OS (32.4 vs 36.1 months, HR 0.98 [95% CI 0.79-1.26], p = 0.98). CONCLUSION: Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/radiotherapy , Cranial Irradiation/methods , Lymphoma/drug therapy , Lymphoma/radiotherapy , Methotrexate/pharmacology , Treatment Outcome , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Protocols , Combined Modality Therapy , Disease-Free Survival , Humans , Male , Methotrexate/administration & dosage , Middle Aged
3.
Neurology ; 81(1): 84-92, 2013 Jul 02.
Article in English | MEDLINE | ID: mdl-23685932

ABSTRACT

OBJECTIVE: To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate-based regimens with or without whole-brain radiotherapy (WBRT). METHODS: Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the χ(2) test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient. RESULTS: The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p = 0.0011), motor skills (p = 0.0023), and neuropsychological composite score (p = 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p = 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p = 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes. CONCLUSIONS: Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Central Nervous System Neoplasms/therapy , Cognition/drug effects , Lymphoma/therapy , Methotrexate/therapeutic use , Quality of Life , Antimetabolites, Antineoplastic/adverse effects , Central Nervous System Neoplasms/pathology , Chemoradiotherapy , Humans , Lymphoma/pathology , Methotrexate/adverse effects , Neuroimaging/methods , Neuropsychological Tests , Prospective Studies
4.
Haematologica ; 98(5): 808-13, 2013 May.
Article in English | MEDLINE | ID: mdl-23144196

ABSTRACT

Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin's lymphoma. However, no prospective data are available concerning the feasibility and efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) of these patients were treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. The median overall survival was 7 months (95% confidence interval 2.6-11.4), being 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years old. The 1-year survival rate was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both undergoing transplantation and survival. In conclusion, despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Long-term survival is, however, possible and more likely in patients able to undergo stem cell transplantation.


Subject(s)
Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/therapy , Lymphoma, Non-Hodgkin/pathology , Lymphoma, Non-Hodgkin/therapy , Neoplasm Recurrence, Local/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/mortality , Disease Progression , Female , Hematopoietic Stem Cell Transplantation , Humans , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Prognosis , Retrospective Studies , Treatment Outcome , Young Adult
5.
Anticancer Res ; 31(1): 317-23, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21273617

ABSTRACT

BACKGROUND: A randomized phase II trial was conducted to determine if two non-platinum protocols are able to yield a similar efficacy and toxicity profile as compared to two platinum-based doublets in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 61 patients were randomly assigned to a reference regimen of carboplatin and paclitaxel (repeated every 3 weeks) or to one of three experimental regimens: paclitaxel plus vinorelbine (repeated every 3 or 4 weeks) and carboplatin plus paclitaxel (repeated every 4 weeks). RESULTS: The objective remission rate for all the patients was 34.1%. The median progression-free survival for all the patients was 3 months. The median overall survival and one-year overall survival were 6 months and 21.5%, respectively. Toxicity was moderate and manageable. Response, survival and toxicity did not significantly differ between the four treatment groups. CONCLUSION: The efficacy and toxicity profile of platinum-free combinations is comparable to that of platinum-based doublets.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Large Cell/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Carboplatin/administration & dosage , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Remission Induction , Survival Rate , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
6.
Lancet Oncol ; 11(11): 1036-47, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20970380

ABSTRACT

BACKGROUND: High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. METHODS: Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. FINDINGS: 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). INTERPRETATION: No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/radiotherapy , Cranial Irradiation , Lymphoma/drug therapy , Lymphoma/radiotherapy , Methotrexate/administration & dosage , Aged , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/mortality , Chi-Square Distribution , Cranial Irradiation/adverse effects , Cytarabine/administration & dosage , Disease-Free Survival , Dose Fractionation, Radiation , Female , Germany , Humans , Ifosfamide/administration & dosage , Kaplan-Meier Estimate , Lymphoma/mortality , Male , Methotrexate/adverse effects , Middle Aged , Proportional Hazards Models , Radiotherapy, Adjuvant , Risk Assessment , Risk Factors , Survival Rate , Time Factors , Treatment Outcome
7.
Expert Rev Neurother ; 9(10): 1497-509, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19831839

ABSTRACT

Despite recent advances in diagnosis and treatment, the prognosis of primary CNS lymphoma (PCNSL) and CNS relapse of systemic non-Hodgkin lymphoma remains poor, and the optimal treatment is yet to be defined. This review presents an overview of the current status of CNS lymphoma treatment. Treatment options include radiotherapy alone, intravenous conventional chemotherapy alone, intrathecal chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, combined modality treatment (i.e., chemotherapy plus radiotherapy), immunotherapy, radioimmunotherapy and ocular radiation and/or chemotherapy for intraocular lymphoma. High-dose methotrexate remains an essential part of most first-line treatments for PCNSL and CNS relapse of systemic non-Hodgkin lymphoma. Treatment standardization is hampered by the rarity of the disease and the difficulty of conducting trials with a higher number of patients. However, a recently closed Phase III/IV trial will most likely define the role of adjuvant whole-brain radiation treatment in PCNSL. Future directions in the management of PCNSL and CNS relapse of systemic lymphoma may include treatment stratification according to patient age and clinical and biological prognostic factors.


Subject(s)
Central Nervous System Neoplasms/immunology , Central Nervous System Neoplasms/therapy , Combined Modality Therapy/methods , Immunocompetence/physiology , Lymphoma/immunology , Lymphoma/therapy , Central Nervous System Neoplasms/diagnosis , Humans , Lymphoma/diagnosis , Magnetic Resonance Imaging/methods
8.
J Clin Oncol ; 27(21): 3503-9, 2009 Jul 20.
Article in English | MEDLINE | ID: mdl-19451444

ABSTRACT

PURPOSE Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. PATIENTS AND METHODS This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age > or = 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS > or = 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. CONCLUSION This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.


Subject(s)
Blood-Brain Barrier/physiology , Central Nervous System Neoplasms/drug therapy , Infusions, Intra-Arterial/methods , Methotrexate/administration & dosage , Antimetabolites, Antineoplastic , Brain Neoplasms/diagnosis , Brain Neoplasms/physiopathology , Central Nervous System Neoplasms/complications , Central Nervous System Neoplasms/diagnosis , Disease-Free Survival , Drug Delivery Systems , Humans , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/metabolism , Methotrexate/therapeutic use , Osmosis , Prognosis , Treatment Outcome
9.
Neuro Oncol ; 11(5): 503-13, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19158414

ABSTRACT

To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m(2) (n = 6), (3) rituximab 375 mg/m(2) (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment T2/FLAIR MRI) and resulted in stable disease (50%-125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only one of six animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Central Nervous System Neoplasms/drug therapy , Lymphoma, B-Cell/drug therapy , Magnetic Resonance Imaging/methods , Methotrexate/administration & dosage , Animals , Antibodies, Monoclonal, Murine-Derived , Cell Line, Tumor , Female , Humans , Image Enhancement , Rats , Rats, Nude , Rituximab , Treatment Outcome , Xenograft Model Antitumor Assays
10.
Neuro Oncol ; 11(4): 423-9, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19060176

ABSTRACT

Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood-brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 ((90)Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the (90)Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 ((111)In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of

Subject(s)
Antibodies, Monoclonal/therapeutic use , Central Nervous System Neoplasms/radiotherapy , Neoplasm Recurrence, Local/radiotherapy , Radioimmunotherapy , Adult , Aged , Antibodies, Monoclonal/pharmacokinetics , Central Nervous System Neoplasms/immunology , Central Nervous System Neoplasms/pathology , Female , Humans , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/radiotherapy , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/radiotherapy , Male , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathology , Prognosis , Prospective Studies , Remission Induction , Survival Rate , Tissue Distribution , Yttrium Radioisotopes/therapeutic use
11.
J Neurooncol ; 93(2): 213-7, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19099202

ABSTRACT

We evaluated response, progression-free survival (PFS), overall survival (OS), relapse patterns and long-term toxicity of intraocular lymphoma (IOL) patients treated with ifosfamide (IFO) or trofosfamide (TRO). In a prospective single center study, IFO or TRO were given to 10 patients with IOL. The median patient age was 73 (range 46-83) years. Six patients were pretreated with up to four treatment regimens for ocular or cerebral lymphoma, and four were therapy-naive. All patients responded, including nine complete remissions and one partial remission, with a median PFS of 18 (7-36) months. Seven patients relapsed: five in the eye and two in the brain. Median OS was 32 (7-37+) months. No long-term toxicity was observed in patients treated with IFO or TRO alone. IFO or TRO were active and well tolerated in this study. Thus, they may represent suitable combination partners for other cytostatics used for PCNSL and IOL treatment.


Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Cyclophosphamide/analogs & derivatives , Eye Neoplasms/drug therapy , Ifosfamide/therapeutic use , Lymphoma/drug therapy , Aged , Aged, 80 and over , Cyclophosphamide/therapeutic use , Eye Neoplasms/mortality , Eye Neoplasms/surgery , Follow-Up Studies , Humans , Lymphoma/mortality , Lymphoma/surgery , Middle Aged , Survival Analysis , Survivors , Time Factors , Vitrectomy
12.
Neuro Oncol ; 11(2): 142-50, 2009 Apr.
Article in English | MEDLINE | ID: mdl-18772353

ABSTRACT

To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m(2) (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7-10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Disease Models, Animal , Glioma/drug therapy , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Bevacizumab , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Carboplatin/administration & dosage , Glioma/mortality , Glioma/pathology , Humans , Magnetic Resonance Imaging , Male , Rats , Rats, Nude , Survival Rate , Tumor Burden
13.
Ann Hematol ; 88(2): 133-9, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18679681

ABSTRACT

Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m(2) of MTX (4 h infusion on day 1) and 1.5-2 g/m(2)/day of IFO (3 h infusion on days 3-5). The study included 20 patients with a median age of 65 years (range, 30-83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/drug therapy , Ifosfamide/therapeutic use , Lymphoma/drug therapy , Methotrexate/therapeutic use , Adult , Aged , Aged, 80 and over , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Humans , Lymphoma/diagnostic imaging , Lymphoma/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Survival Rate , Tomography, X-Ray Computed , Treatment Outcome
14.
Cancer ; 112(3): 581-8, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18072268

ABSTRACT

BACKGROUND: The rate of durable responses in embryonal and certain germ cell tumors of the central nervous system (CNS) is unsatisfactory. Intraarterial chemotherapy and osmotic blood-brain barrier disruption (IA/BBBD) increases drug delivery to the CNS. METHODS: Data of patients treated with carboplatin or methotrexate-based IA/BBBD on prospective phase 2 trials conducted at 3 centers were collected. Study outcomes included overall survival (OS), time to progression (TTP), and toxicity. RESULTS: Fifty-four patients were treated. Twenty-seven patients received IA/BBBD as salvage treatment. The median OS was 2.8 years for all patients, 2.5 years for supratentorial and disseminated primitive neuroectodermal tumors (PNETs, n = 29), 1.7 years for medulloblastomas (n = 12), and 5.4 years for germ cell tumors (n = 13). OS and TTP for all patients were better with a Karnofsky Performance Status > or =70% (P = .0013 and .0070) and IA/BBBD as first-line treatment (P = .0059 and .029). In PNETs, OS was higher with pineal location (P = .045) and IA/BBBD as first-line treatment (P = .0036), and TTP was improved with radiotherapy before IA/BBBD (P = .036) and IA/BBBD as first-line treatment (P = .0079). Seventeen of 54 patients (31%) are alive, and 16 are alive at 4+ to 18+ years. Three survivors were not treated with radiotherapy and 4 were treated with focal radiotherapy only. The patients who were not irradiated did not develop dementia. CONCLUSIONS: Survival and toxicity data appear promising, considering the cohort's adverse prognostic profile. A plateau in survival curves suggests a cure for some patients. Long-term survival may be achieved with focal or reduced-dose radiotherapy in some IA/BBBD patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood-Brain Barrier/physiopathology , Central Nervous System Neoplasms/drug therapy , Neoplasms, Germ Cell and Embryonal/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Central Nervous System Neoplasms/radiotherapy , Child , Child, Preschool , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease Progression , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Infant , Infusions, Intra-Arterial/methods , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Neoplasms, Germ Cell and Embryonal/radiotherapy , Prospective Studies , Survival Analysis , Treatment Outcome
15.
Blood ; 111(3): 1085-93, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-17962515

ABSTRACT

Isolated central nervous system (CNS) relapse involving the brain parenchyma is a rare complication of systemic non-Hodgkin lymphoma. We retrospectively analyzed patient characteristics, management, and outcomes of this complication. After complete response to initial non-Hodgkin lymphoma treatment, patients with isolated CNS relapse with the brain parenchyma as initial relapse site were eligible. Patients with isolated CNS relapse involving only the cerebrospinal fluid were not eligible. Information on 113 patients was assembled from 13 investigators; 94 (83%) had diffuse large B-cell lymphoma. Median time to brain relapse was 1.8 years (range, 0.25-15.9 years). Brain relapse was identified by neuroimaging in all patients; in 54 (48%), diagnostic brain tumor specimen was obtained. Median overall survival from date of brain relapse was 1.6 years (95% confidence interval, 0.9-2.6 years); 26 (23%) have survived 3 years or more. Median time to progression was 1.0 year (95% confidence interval, 0.7-1.7 years). Age less than 60 years (P = .006) at relapse and methotrexate use (P = .008) as front-line treatment for brain relapse were significantly associated with longer survival in a multivariate model. Our results suggest systemic methotrexate is the optimal treatment for isolated CNS relapse involving the brain parenchyma. Long-term survival is possible in some patients.


Subject(s)
Brain Neoplasms/secondary , Central Nervous System Neoplasms/secondary , Lymphoma, Non-Hodgkin/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Brain Neoplasms/surgery , Brain Neoplasms/therapy , Cerebral Hemorrhage , Female , Humans , Lymphoma, Non-Hodgkin/classification , Lymphoma, Non-Hodgkin/surgery , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Recurrence
16.
Leuk Lymphoma ; 48(9): 1712-20, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17786706

ABSTRACT

Five patients with relapsed PCNSL were given chemo-immunotherapy (rituximab followed by carboplatin and methotrexate) with osmotic blood-brain barrier (BBB) opening. Four patients achieved CR and one patient had stable disease. Two patients (2/5) had durable responses (survival: 230+, 122+, 82, 42, 38 weeks). One patient later received Indium-111-ibritumomab tiuxetan and Yttrium-90-ibritumomab tiuxetan intravenous, without BBB opening. There was good uptake of Indium-111 ibritumomab tiuxetan in tumor on SPECT scan after 48 h. Estimated radiation doses to brain around and distant from tumor were within safe limits. After Ytrium-90 ibritumomab tiuxetan there was CR in enhancing tumor where the BBB was leaky, but lesions occurred in other brain regions, where the BBB was intact during Yttrium-90 ibritumomab tiuxetan infusion. Imaging and dosimetry with Indium-111 ibritumomab tiuxetan and efficacy with Yttrium-90 ibritumomab tiuxetan suggest the need for future enhanced CNS delivery when using monoclonal or radiolabeled antibodies, as intravenous delivery alone may provide modest clinical benefit due to limited BBB permeability.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Brain Neoplasms/therapy , Lymphoma, Non-Hodgkin/therapy , Radioimmunotherapy , Yttrium Radioisotopes/therapeutic use , Adult , Aged , Blood-Brain Barrier , Carboplatin/administration & dosage , Combined Modality Therapy , Female , Humans , Indium Radioisotopes/therapeutic use , Male , Methotrexate/administration & dosage , Middle Aged
17.
J Clin Oncol ; 25(16): 2295-305, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17538176

ABSTRACT

PURPOSE: This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006. RESULTS: Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking. CONCLUSION: In this article, we review drug delivery across the BBB, as well as blood-tumor and -cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Brain Neoplasms/drug therapy , Drug Delivery Systems , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/cerebrospinal fluid , Blood-Brain Barrier , Brain/metabolism , Humans
18.
Clin Cancer Res ; 13(8): 2504-11, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17438111

ABSTRACT

PURPOSE: The incidence of primary central nervous system lymphoma (PCNSL) is increasing. Therapeutic approaches remain controversial. An animal model that mimics the clinical situation would be useful for evaluating PCNSL biology and treatment. EXPERIMENTAL DESIGN: Nude rats received intracerebral (caudate nucleus, n = 49) or intraventricular (n = 4) inoculation of human B-lymphoma cell line MC116. Two to five weeks after tumor inoculation, magnetic resonance imaging (MRI) was done (n = 24), and rat brains were assessed for pathology. Five rats each received whole-brain radiotherapy (WBRT, 20 Gy) or high-dose i.v. methotrexate (3 g/m2). RESULTS: Intracerebral tumors developed in 84% of evaluable animals with no pretreatment, 79% of rats pretreated with 4 Gy total body irradiation, and 92% of rats pretreated with cyclophosphamide (300 mg/m2). MRI showed abnormal T2 signal and gadolinium enhancement on T1-weighted images, consistent with tumor growth 19 to 24 days after inoculation. Tumor cells staining positively for B-lymphoma markers infiltrated within the inoculated hemisphere, along fiber tracks to the contralateral hemisphere, and along the subarachnoid space and ventricles. Tumors showed reactive gliosis. Intraventricular tumor cell injection resulted in periventricular parenchymal infiltration in both hemispheres. Radiation and methotrexate were effective in vitro, but only WBRT was clearly effective after 1 week in the intracerebral model. CONCLUSION: This model closely mimics human PCNSL in terms of imaging, histology, and treatment sensitivity and will be useful for the development of future therapeutic strategies for PCNSL.


Subject(s)
Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/radiotherapy , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/radiotherapy , Animals , Cell Line, Tumor , Disease Models, Animal , Humans , Magnetic Resonance Imaging , Rats , Rats, Nude , Transplantation, Heterologous , Whole-Body Irradiation
19.
Clin Ophthalmol ; 1(3): 247-58, 2007 Sep.
Article in English | MEDLINE | ID: mdl-19668478

ABSTRACT

Despite recent advances in diagnosis and treatment, the prognosis of primary intraocular lymphoma (PIOL) remains poor, and the optimal treatment has yet to be defined. This review presents an overview of the current status of PIOL with a focus on recent advances in diagnosis and treatment. Recent studies show a decreasing time interval from symptom presentation to diagnosis, likely due to increased awareness of the disease and improved diagnostic tools. Advances in the pathologic characterization of PIOL have been made over the past years, and the development of PIOL animal models can offer the opportunity to study aspects of PIOL pathology, pathogenesis and treatment. Regarding treatment of PIOL, recent larger case series favor the use of systemic chemotherapy plus local ocular treatment as first-line management for patients with concomitant PIOL and PCNSL. For patients with isolated PIOL, the current trend focuses on local first-line treatment and early diagnosis of PIOL. Future studies are needed to confirm these trends. Future directions in the management of PIOL should include studies about pathogenesis, prognostic factors, and treatment optimization. In the future, monoclonal antibodies and radioimmunotherapy could prove useful for PIOL treatment.

20.
Neurosurg Focus ; 21(5): E11, 2006 Nov 15.
Article in English | MEDLINE | ID: mdl-17134113

ABSTRACT

The optimal treatment of primary central nervous system lymphoma (PCNSL), a rare form of extranodal non-Hodgkin lymphoma, has yet to be defined. Whole-brain radiation therapy (WBRT) has limited efficacy as a single therapeutic modality and is associated with a high risk of delayed neurotoxicity. Methotrexate-based chemotherapy regimens yield poor drug penetration across the blood-brain barrier (BBB), thus necessitating administration of high doses with the concomitant risk of increased systemic and neurological toxicity. Combined-modality therapy (WBRT plus chemotherapy) can improve response and survival rates, yet it is associated with a high risk of neurotoxicity. The aim of chemotherapy in conjunction with BBB disruption is to maximize drug delivery to the brain and improve the agent's efficacy, while preserving neurocognitive function and minimizing systemic toxicity. Methotrexate-based chemotherapy regimens administered in conjunction with BBB disruption have shown promising results in PCNSL. Animal models of central nervous system lymphoma and drug neurotoxicity offer new possibilities to study the effects of various treatments on PCNSL and normal brain and can also help understand biological and pathophysiological aspects of this disease. Because the intact BBB is even less permeable to antibodies than it is to drugs, preclinical and clinical studies of monoclonal antibody delivery (for example, rituximab and 90Y ibritumomab tiuxetan) to the brain in conjunction with BBB disruption offer a new possibility to make these novel treatments more efficient against PCNSL. Regarding the evaluation of more sensitive and specific diagnostic imaging tools, iron oxide-based contrast agents for magnetic resonance imaging have shown promise for better differentiation of PCNSL from other white matter diseases.


Subject(s)
Blood-Brain Barrier , Brain Neoplasms/blood supply , Brain Neoplasms/physiopathology , Lymphoma, Non-Hodgkin/physiopathology , Animals , Brain Neoplasms/therapy , Humans , Lymphoma, Non-Hodgkin/therapy
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