ABSTRACT
To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m2), high-dose cytarabine (2 × 3 g/m2) and thiotepa (40 mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m2, carmustine 400 mg/m2 and thiotepa (4 × 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Lymphoma/pathology , Lymphoma/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain/diagnostic imaging , Brain/pathology , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/mortality , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Lymphoma/diagnostic imaging , Lymphoma/mortality , Male , Middle Aged , Prospective Studies , Recurrence , Retreatment , Transplantation, Autologous , Treatment OutcomeABSTRACT
BACKGROUND: Some important knowledge has recently been gained on primary central nervous system lymphomas (PCNSL) despite its rarity. GOAL: This article summarizes the most relevant progress in the diagnostics and therapy of PCNSL and discusses future directions. MATERIAL AND METHODS: Reference articles in the English language literature were studied with respect to future approaches in PCNSL. RESULTS: New diagnostic methods in cerebrospinal fluid have been developed to facilitate lymphoma diagnosis; however, their value still has to be validated. A better immunohistological and molecular characterization of PCNSL will probably result in identification of new therapeutic targets. The only phase III trial for PCNSL completed so far did not demonstrate a survival advantage with whole brain irradiation after high-dose methotrexate (HDMTX)-based chemotherapy as compared to chemotherapy alone. The optimal primary chemotherapy has not yet been established due to a lack of results from randomized trials. Non-comparative studies suggest a superiority of combined polychemotherapy over HDMTX monotherapy. Future therapeutic developments are directed towards consolidation of HDMTX-based induction chemotherapy with noncross-resistant conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. An important goal of all therapies for PCNSL is to avoid delayed neurotoxicity. DISCUSSION: Further improvement of diagnostics and well-designed comparative studies, including new drugs when possible are still needed to define the optimal management of this still frequently prognostically unfavorable disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/diagnosis , Brain Neoplasms/therapy , Chemoradiotherapy/methods , Lymphoma/diagnosis , Lymphoma/therapy , Antineoplastic Agents/administration & dosage , Evidence-Based Medicine , Humans , Methotrexate/administration & dosage , Molecular Diagnostic Techniques/methods , Treatment OutcomeABSTRACT
BACKGROUND: Intraocular lymphomas are very rare and occur as either vitreoretinal or uveal tumors. Management in the clinical routine is highly variable and controversial. OBJECTIVES: To present the most important aspects of the diagnostics and therapy from the perspective of hematological oncologists and formulate management recommendations. METHODS: The English language literature was reviewed and the most important data were analyzed for presentation. RESULTS: In patients with vitreoretinal lymphoma evaluation for central nervous system (CNS) involvement should be performed due to its strong association with primary CNS lymphoma (PCNSL). The prognosis is relatively poor, particularly when the CNS is involved. Optimal therapy has not yet been established. For isolated vitreoretinal manifestations local therapy, such as intraocular methotrexate (MTX) or rituximab or radiation is recommended; however, there is a very high frequency of CNS relapse. Systemic high-dose MTX-based chemotherapy analogous to PCNSL treatment is an alternative option and is the treatment of choice in patients with simultaneous CNS and vitreoretinal lymphoma. Primary uveal lymphoma is usually an indolent lymphoma and treated by local therapy, whereas secondary uveal lymphoma predominantly occurs in aggressive systemic (non-CNS) lymphoma and is treated by systemic chemotherapy. DISCUSSION: Data on intraocular lymphoma are derived from small, usually retrospective and very heterogeneous studies with a relatively short follow-up. To gain more knowledge on this rare disease, inclusion of patients in the prospective registry, currently in progress in Germany, is desirable.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/therapy , Eye Neoplasms/diagnosis , Eye Neoplasms/therapy , Lymphoma/diagnosis , Lymphoma/therapy , Antineoplastic Agents/therapeutic use , Diagnosis, Differential , Humans , Neoplasm InvasivenessABSTRACT
Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.
Subject(s)
Central Nervous System Neoplasms/genetics , Herpesvirus 4, Human/genetics , Lymphoproliferative Disorders/genetics , MicroRNAs/genetics , Transcriptome , Cell Line, Transformed , Central Nervous System Neoplasms/virology , Female , Gene Expression Profiling , Humans , Lymphoproliferative Disorders/virology , MaleABSTRACT
BACKGROUND: We evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial. PATIENTS AND METHODS: MD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI). RESULTS: Data on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MD-). There was a significant correlation of MD with CSF pleocytosis (>5/µl; P < 0.0001), but no correlation with CSF protein elevation (>45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0-14.5] in MD+ and 8.3 months (5.7-10.8) in MD- patients (P = 0.95); median overall survival was 21.5 months (95% CI 16.8-26.1) and 24.9 months (17.5-32.3), respectively (P = 0.98). CONCLUSION: MD was detected infrequently and had no impact on outcome in this trial.
Subject(s)
Central Nervous System Neoplasms/pathology , Meningeal Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/therapy , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lymphoma , Male , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/mortality , Meningeal Neoplasms/therapy , Middle Aged , Prognosis , Randomized Controlled Trials as Topic , Young AdultABSTRACT
Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.
Subject(s)
Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/therapy , HumansABSTRACT
BACKGROUND: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. PATIENTS AND METHODS: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. RESULTS: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. CONCLUSIONS: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzothiazoles/therapeutic use , Epothilones/therapeutic use , Neoplasms/drug therapy , Salvage Therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Benzothiazoles/pharmacokinetics , Drug Resistance, Neoplasm , Epothilones/pharmacokinetics , Feasibility Studies , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Survival Rate , Tissue Distribution , Treatment OutcomeABSTRACT
BACKGROUND: The impact of meningeal dissemination in primary CNS lymphoma (PCNSL) is debated, and the reported frequency varies. We prospectively evaluated the diagnostic value of PCR in comparison with CSF cytomorphology and MRI for diagnosing meningeal dissemination in PCNSL. METHODS: We evaluated 282 patients from a multicenter therapy study for PCNSL for the presence of meningeal dissemination: 205 with CSF cytomorphology, 171 with PCR of the rearranged immunoglobulin heavy-chain genes in CSF, and 217 with cranial MRI. RESULTS: Meningeal dissemination was found in 33 of 205 patients (16%) by cytomorphology, in 19 of 171 (11%) patients evaluated by PCR, and in 8 of 217 patients (4%) by MRI. Considering either of these methods, the relative frequency of meningeal dissemination was 17.4% (49 of 282 patients). PCR was monoclonal in 6 of 19 (32%) samples with positive cytomorphology, 1 of 13 samples (8%) with suspicious cytology, and in 10 of 105 (10%) cytologically negative samples. In 11 samples with positive and 12 with suspicious cytology, PCR showed only a polyclonal pattern. The probability of meningeal dissemination detection was higher in cases with CSF pleocytosis (>5/microL) with an OR of 2.48 (95% CI 1.15-5.34, p = 0.018). CSF protein had no predictive value for meningeal dissemination detection. CONCLUSIONS: We found a low rate of meningeal dissemination in primary CNS lymphoma in this large prospective study. The rate of discordant PCR and cytomorphologic results was high. Thus, the methods should be regarded as complementary. CSF pleocytosis had predictive value for meningeal dissemination detection.
Subject(s)
Lymphoma/diagnosis , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/secondary , Neoplasm Metastasis/diagnosis , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain/pathology , Cell Count/statistics & numerical data , Combined Modality Therapy , Cytological Techniques/statistics & numerical data , Female , Humans , Immunoglobulin Heavy Chains/analysis , Immunoglobulin Heavy Chains/blood , Lymphoma/immunology , Lymphoma/therapy , Magnetic Resonance Imaging/statistics & numerical data , Male , Meningeal Neoplasms/immunology , Meninges/pathology , Middle Aged , Neoplasm Metastasis/immunology , Polymerase Chain Reaction/statistics & numerical data , Predictive Value of Tests , Prospective Studies , Reproducibility of ResultsABSTRACT
Light chain deposition disease (LCDD) is a form of monoclonal immunoglobulin deposition diseases (MIDD) which in contrast to light-chain derived (AL) amyloidosis is characterized by non-congophilic, non-fibrillary monoclonal protein deposits. Systemic organ deposits are common with the kidney being a major target organ. A clonal lymphoplasmocytic proliferation, e.g. plasmacytoma, is present in the majority of cases. Here we report on a 19-year-old male who presented with generalized seizures and an enhancing white matter lesion on MRI scans. A stereotactic brain biopsy revealed a low-grade B cell lymphoma with plasmacellular differentiation as well as lambda light chain deposits without birefringence under polarized microscopy. No systemic lymphoma manifestations or systemic light chain deposits were found, nor was a monoclonal gammopathy detectable in serum and urine. After systemic chemotherapy with three courses high-dose methotrexate the size of the lesion and the condition of the patient have remained stable for 24 months now. This is the first description of cerebral LCDD developing without systemic disease in conjunction with the diagnosis of a cerebral low-grade B cell lymphoma. We present the clinical, laboratory and radiological findings and discuss the pathogenesis of this unusual LCDD manifestation.
Subject(s)
Brain Diseases/pathology , Brain Edema/pathology , Brain Neoplasms/pathology , Immunoglobulin Light Chains/adverse effects , Immunoglobulin Light Chains/metabolism , Lymphoma, B-Cell/pathology , Paraproteinemias/pathology , Adult , Anticonvulsants/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Brain Diseases/complications , Brain Diseases/drug therapy , Brain Diseases/metabolism , Brain Edema/etiology , Brain Neoplasms/complications , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Carbamazepine/therapeutic use , Humans , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/metabolism , Male , Methotrexate/therapeutic use , Ocular Motility Disorders/etiology , Paraproteinemias/complications , Paraproteinemias/drug therapy , Paraproteinemias/metabolism , Seizures/drug therapy , Seizures/etiology , Seizures/pathology , Treatment Outcome , Unconsciousness/etiology , Unconsciousness/pathologyABSTRACT
BACKGROUND: Standard salvage therapy has not been established for recurrent primary central nervous system lymphoma (PCNSL). We report the final results of a prospective study on topotecan chemotherapy in relapsed or refractory PCNSL. PATIENTS AND METHODS: The study included 27 patients with a median age of 51 years and an ECOG performance status of 2. Fourteen patients were refractory to the last therapy, and 13 relapsed after a median period of 6.0 months. Pretreatment with up to four regimens included chemotherapy in 26 patients and whole brain irradiation in 14. A 30-min daily topotecan infusion of 1.5 mg/m(2) for 5 days was repeated every 3 weeks. RESULTS: The response rate was 33% with five complete (CR) and four partial remissions (PR). The median follow-up was 37.7 months. All complete responders had sustained remissions lasting for 9 to 28 months. The median event-free survival (EFS) was 2.0 months (9.1 months in responders), the overall survival (OAS) was 8.4 months. CTC grade 3-4 leukopenia occurred in 26% and thrombocytopenia in 11% of the patients. Eight of 12 patients alive without cerebral lymphoma > or = six months after topotecan exhibited deficits attributable to late neurotoxicity. CONCLUSION: Topotecan as monotherapy is active in relapsed and refractory PCNSL with tolerable toxicity.
Subject(s)
Antineoplastic Agents/therapeutic use , Central Nervous System Neoplasms/drug therapy , Lymphoma/drug therapy , Salvage Therapy , Topotecan/therapeutic use , Adult , Aged , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/radiotherapy , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Lymphoma/mortality , Lymphoma/radiotherapy , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Prospective Studies , Remission Induction , Survival AnalysisABSTRACT
BACKGROUND: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has not yet been defined. The study assesses ifosfamide (IFO) and trofosfamide (TRO) for treating IOL. PATIENTS AND METHODS: We prospectively evaluated the efficacy and aqueous penetration of intravenous IFO, oral TRO and their active 4-hydroxy (4-OH) metabolites in 10 patients with IOL. Doses varied from 1500 to 2000 mg/m2/day on days 1-3 for IFO and from 150 to 400 mg/day (continuous or intermittent administration) for TRO. Four patients had newly diagnosed disease, and six had relapsed after pretreatment. RESULTS: All patients responded to first treatment with IFO or TRO, and both of two patients responded to re-treatment with IFO on ocular relapse. Progression-free survival from the first treatment with IFO or TRO was > or = 6-18 months. In six of six patients, 4-OH metabolites were detected in the aqueous humor at a concentration of 0.32-1.56 microM immediately after IFO infusion with an aqueous/serum ratio of 0.19-0.54. 4-OH metabolites could be detected in one of three patients at a concentration of 7.2 microM 3-16 h after ingestion of TRO. CONCLUSIONS: IFO and TRO are active in IOL. IOL patients evidence aqueous penetration of 4-OH metabolites after intravenous administration of IFO.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Cyclophosphamide/analogs & derivatives , Eye Neoplasms/metabolism , Ifosfamide/pharmacokinetics , Lymphoma, B-Cell/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Aged , Cyclophosphamide/pharmacokinetics , Disease-Free Survival , Eye Neoplasms/drug therapy , Eye Neoplasms/pathology , Humans , Infusions, Intravenous , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Middle Aged , Prospective Studies , Salvage TherapyABSTRACT
BACKGROUND: The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. PATIENTS AND METHODS: One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m(2) HDMTX followed by leucovorin rescue. RESULTS: Toxicity was generally mild with toxicities of WHO grade > or =3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and < or =60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients < or =60 years and those >60 years old (18% versus 44%; P = 0.001). CONCLUSIONS: HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Central Nervous System Neoplasms/drug therapy , Lymphoma/drug therapy , Methotrexate/adverse effects , Methotrexate/therapeutic use , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Central Nervous System Neoplasms/pathology , Female , Glomerular Filtration Rate , Humans , Lymphoma/pathology , Male , Methotrexate/administration & dosage , Methotrexate/pharmacokinetics , Middle Aged , Treatment OutcomeABSTRACT
The authors treated 16 immunocompetent patients with refractory or relapsed primary CNS lymphoma with topotecan. Fifteen patients had been pretreated with up to three chemotherapy regimens, three of them additionally with whole brain irradiation (WBI), and one with WBI alone. Four complete remissions and two partial remissions were achieved. Progression-free survival was 20% at 6 months and 13% at 12 months.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Salvage Therapy , Topotecan/therapeutic use , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/radiotherapy , Combined Modality Therapy , Cranial Irradiation , Disease-Free Survival , Enzyme Inhibitors/therapeutic use , Female , Humans , Lymphoma, Non-Hodgkin/radiotherapy , Male , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Prospective Studies , Remission Induction , Topoisomerase I Inhibitors , Treatment OutcomeSubject(s)
Anemia, Iron-Deficiency/drug therapy , Erythropoietin/analogs & derivatives , Erythropoietin/therapeutic use , Hemochromatosis/complications , Anemia, Iron-Deficiency/etiology , Anemia, Iron-Deficiency/therapy , Darbepoetin alfa , Erythrocyte Indices , Erythrocyte Transfusion/adverse effects , Erythropoietin/administration & dosage , Ferritins/blood , Hemochromatosis/genetics , Hemoglobins/analysis , Humans , Injections, Subcutaneous , Male , Middle Aged , Phlebotomy/adverse effects , Reticulocyte CountABSTRACT
Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.
Subject(s)
Central Nervous System Neoplasms/immunology , Immunocompetence/immunology , Lymphoma/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/therapy , Combined Modality Therapy , Humans , Lymphoma/therapyABSTRACT
The purpose of this multicentre phase II study was to evaluate the efficacy and toxicity of topotecan in pretreated patients with small-cell lung cancer (SCLC) who relapsed with symptomatic brain metastases. 30 patients with a median age of 62 years were entered into the study. 22 patients received the initially planned dose of 1.5 mg/m(2) topotecan as a 30-min intravenous (i.v.) infusion for 5 consecutive days every 3 weeks. Due to the observed thrombocytopenia, the dose was reduced to 1.25 mg/m(2) in the last 8 patients. All 30 patients were pretreated with chemotherapy: 14 with one and 16 with at least two protocols. 8 patients had prior whole-brain iradiation (WBI): 7 in the prophylactic and 1 in the palliative setting. Concomitant systemic metastases were recorded in 24 patients at the time of brain relapse. Cerebral metastases responded in 33% of patients (10/30; three complete responses (CR) and seven partial responses (PR)). Noteworthy is the fact that response was achieved in 4 of 8 patients pretreated by WBI (3 in prophylactic and 1 in palliative setting). The systemic response rate was 29% (7/24). Median time to progression was 3.1 months (range 0.25-14.2+ months), median survival from the beginning of this study was 3.6 months (range 0.25-14.2+ months). Therapy was generally well tolerated, with myelotoxicity being the most common adverse event. Grade 3 leucocytopenia according to the Common Toxicity Criteria (CTC) occurred in 28% (23/83) of the courses and grade 4 in 22% (18/83). Grade 3 thrombocytopenia was observed in 17% of the courses (14/83) and grade 4 in 11% (9/83). 17% of patients (5/30) had a documented grade 3 infection. These results using topotecan are promising in heavily pretreated patients with SCLC brain metastases and merit further evaluation.
Subject(s)
Antineoplastic Agents/adverse effects , Brain Neoplasms/secondary , Carcinoma, Small Cell/secondary , Cranial Irradiation , Lung Neoplasms , Topotecan/administration & dosage , Adult , Aged , Brain Neoplasms/drug therapy , Brain Neoplasms/prevention & control , Carcinoma, Small Cell/drug therapy , Disease Progression , Hematologic Diseases/chemically induced , Humans , Infusions, Intravenous , Middle Aged , Prospective Studies , Survival Analysis , Topotecan/adverse effectsABSTRACT
BACKGROUND: Cytologic evaluation of CSF does not consistently detect malignant cells in patients with primary CNS lymphoma (PCNSL). The potentially more sensitive molecular assessment of monoclonality has not been shown in CSF samples. METHODS: The authors studied nested PCR of the complementary determining region III (CDR III) on 76 CSF specimens of patients with PCNSL. Patients with systemic disseminated B-cell non-Hodgkin's lymphoma (n = 17) and 17 patients with no history of lymphoma were compared. PCR products were evaluated by automated fluorescent fragment analysis (ALF). RESULTS: In 68 patients with PCNSL, the authors analyzed the first obtained CSF sample. Nevertheless, 60 patients were taking corticosteroids. In 16 PCNSL samples, amplifiable DNA was not yielded. Taking into account that at least two independent assays have to be performed, CDR III PCR consistently revealed monoclonal products in eight PCNSL and polyclonal results in 52 PCNSL specimens. CDR III PCR detected no monoclonal PCR products in patients without history of lymphoma. In 10 patients with PCNSL, the PCR result and the CSF cytology were discordant. Concerning therapeutic impact, leptomeningeal tumor spread did not predict tumor response in this group of patients with PCNSL. CONCLUSIONS: This study performed CDR III PCR as a routine diagnostic technique applicable even on CSF samples with low cell counts. These data present low incidence of leptomeningeal involvement in this subset of pretreated PCNSL patients. Because the CSF evaluation did not predict outcome in our patients, further analysis in patients with PCNSL should focus on CSF samples that are obtained very early after diagnosis.
Subject(s)
Central Nervous System Neoplasms/pathology , Cerebrospinal Fluid/cytology , Complementarity Determining Regions/genetics , Lymphoma, Non-Hodgkin/pathology , Meningeal Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Central Nervous System Neoplasms/genetics , Female , Humans , Lymphoma, Non-Hodgkin/genetics , Male , Meningeal Neoplasms/genetics , Middle Aged , Polymerase Chain Reaction , Prognosis , Prospective StudiesABSTRACT
Treatment and prognosis have not been well characterized in germ cell tumors (GCT) with a malignant nongerm cell component. Patients with a mediastinal tumor, neural or rhabdomyosarcomatous differentiation and distant metastases have the poorest prognosis. We report a rare case of mixed GCT composed of seminoma, teratoma and rhabdomyosarcoma with the rhabdomyosarcomatous component metastasized into the liver and bone marrow (BM) causing hypercalcemia. The patient was treated with differentiation-tailored chemotherapy (CHT) including a disease-adapted high-dose (HD) CHT regimen with purified autologous PBSCT (APBSCT) and pamidronate. To date, remission has lasted for 4 years. Tumor-adapted CHT including HD-CHT with APBSCT can induce long term remissions in high-risk patients with transformed GCT. A review of the literature is given.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Neoplasms, Multiple Primary/drug therapy , Rhabdomyosarcoma/drug therapy , Seminoma/drug therapy , Teratoma/drug therapy , Testicular Neoplasms/drug therapy , Bone Marrow/pathology , Carboplatin/administration & dosage , Cell Differentiation , Cisplatin/administration & dosage , Combined Modality Therapy , Diphosphonates/therapeutic use , Epirubicin/administration & dosage , Etoposide/administration & dosage , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Lumbar Vertebrae , Male , Middle Aged , Neoplasm Metastasis , Neoplasms, Multiple Primary/surgery , Neoplasms, Multiple Primary/therapy , Orchiectomy , Pamidronate , Remission Induction , Rhabdomyosarcoma/pathology , Rhabdomyosarcoma/secondary , Rhabdomyosarcoma/surgery , Rhabdomyosarcoma/therapy , Seizures/etiology , Seminoma/surgery , Seminoma/therapy , Spinal Neoplasms/drug therapy , Spinal Neoplasms/secondary , Spinal Neoplasms/therapy , Teratoma/surgery , Teratoma/therapy , Testicular Neoplasms/surgery , Testicular Neoplasms/therapy , Transplantation, AutologousABSTRACT
The increase in primary CNS lymphoma (PCNSL) has resulted in a growing interest in this disease. Despite efforts to optimize the management of PCNSL, several therapeutic questions remain unanswered. Due to methodological pitfalls in the clinical trials published thus far, particulary their uni- or oligocenter setting and the small number of patients, it has been difficult to draw definitive conclusions. Future efforts should concentrate on identifying optimal chemotherapy combinations, evaluating the efficacy of modern therapy options such as high-dose chemotherapy supported by autologous blood stem cell transplantation, and clarifying the impact of radiotherapy delay in complete responders to chemotherapy. Standardized neuropsychological testing and quality-of-life assessment are indispensable in future PCNSL trials. Important questions regarding management of PCNSL should be preferably addressed in large multicenter prospective randomized trials.
Subject(s)
Central Nervous System Neoplasms/therapy , Lymphoma, Non-Hodgkin/therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Diseases/chemically induced , Brain Diseases/etiology , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/psychology , Cognition Disorders/chemically induced , Cognition Disorders/etiology , Combined Modality Therapy , Cranial Irradiation/adverse effects , Disease-Free Survival , Gene Rearrangement , Humans , Injections, Spinal , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/mortality , Methotrexate/administration & dosage , Methotrexate/adverse effects , Methotrexate/therapeutic use , Radiation Injuries/etiology , Randomized Controlled Trials as Topic , Survival Analysis , Treatment OutcomeABSTRACT
A 79 year-old female patient presented with immunoblastic B-cell lymphoma of the ethmoidal sinuses and destruction of the anterior cranial fossa. After 3 cycles of high-dose methorexate (HD-MTX) MTX serum level remained elevated and creatinine serum levels raised. The patient received Carboxypeptidase G2 (CPG2) intravenously. Within one hour the MTX serum level decreased to <1 micromol/l as determined by high pressure liquid chromatography (HPLC). The patient recovered without significant toxicity and attained a long lasting ongoing (>14 months) complete remission. In this case we were able to demonstrate that rescue from HD-MT nephrotoxicity by CPG2 is also safe and effective in patients with advanced age with impaired renal function. With the help of CPG2, sufficient and potentially curative therapy with HD-MTX may also be provided to patients with a high risk of renal failure.