levoleucovorin and Central-Nervous-System-Neoplasms

Neurotoxicity after the administration of methotrexate continues to worry physicians. However, inadequate folinic acid rescue is often not considered as a cause of this complication. To clarify whether adequate folinic acid rescue prevents methotrexate-induced neurotoxicity without reducing the cure rate in childhood ALL, published evidence that supported or refuted this claim was investigated. A literature search was conducted and the authors of the relevant studies were contacted. The published data supported the contention that neurotoxicity can be prevented by adequate folinic acid rescue even after very high doses of methotrexate. The safe minimum dose of folinic acid can be defined in terms of the dose of methotrexate given; the time to start of rescue is probably less important. There was no evidence that higher doses of folinic acid, such as those used after methotrexate in the treatment of osteosarcoma, rescue leukemia cells. No change in cure rate was found in relation to changes in scheduling or clinically relevant doses of folinic acid rescue. The accumulation of folinic acid in the cerebrospinal fluid did not seem to be of clinical relevance. No studies indicate that doses of folinic acid after high-dose methotrexate administration interfere with the killing of leukemia cells, nor that delaying the start of rescue beyond a certain point increases the antileukemic effect; neurotoxicity will, however, be increased. Review of current protocols that use low-dose folinic acid rescue and are associated with neurotoxicity is highly recommended.

Topics: Central Nervous System Neoplasms; Child; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The majority of the available data on primary central nervous system lymphoma (PCNSL) derive from small unicentric or oligocentric studies. In this multicentre study, we evaluated the response, survival and toxicity in PCNSL patients after carmustine, methotrexate 1.5 g/m2, procarbazine and dexamethasone (BMPD) chemotherapy and searched for prognostic factors. Fifty-six patients received the BMPD protocol (dexamethasone was given only in course 1). The overall complete response rate to chemotherapy was 61% (34/56). Ten complete responders received whole-brain irradiation and 24 were not irradiated. Responders to chemotherapy had significantly longer median overall survival than non-responders (18.2 vs. 9.9 months, P = 0.02). Median survival was significantly longer at institutions accruing at least four patients than at those with fewer patients (31.5 vs. 9.5 months, P = 0.03).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Central Nervous System Neoplasms; Combined Modality Therapy; Dexamethasone; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Procarbazine; Survival Rate; Treatment Outcome

Acute, subacute, and chronic neurologic complications have been reported in children treated with high-dose methotrexate for various malignant diseases. It was the aim of this study to monitor central nervous system treatment with high-dose methotrexate in children with acute lymphoblastic leukemia by serial electroencephalographic (EEG) examinations. Electroencephalographic examinations with quantitative computed analysis were performed in 21 children before and on the third day after each of four high-dose methotrexate infusions with leucovorin rescue according to protocol M of trial ALL-BFM 90 of the German Society for Pediatric Haematology and Oncology. Six patients with a medium risk of relapse also received L-asparaginase. In the cohort treated with methotrexate solely, no statistically significant changes of the quantitative EEG parameters could be demonstrated. Only two children with delayed serum methotrexate clearance showed reversible diffuse EEG slowing of a slight to moderate degree. In the group with additional L-asparaginase treatment, slight transient EEG slowing also occurred. Our findings indicate that in patients with a normal methotrexate clearance during central nervous system treatment with high-dose methotrexate according to trial BFM-ALL 90, usually no subacute or cumulative EEG changes have to be expected. If neurologic or psychiatric symptoms or EEG slowing occur, delayed methotrexate clearance must be suspected.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain; Central Nervous System Neoplasms; Child; Child, Preschool; Electroencephalography; Female; Humans; Infant; Injections, Intravenous; Injections, Spinal; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Patients with primary central-nervous-system lymphoma (PCNSL) are treated with chemotherapy and cranial irradiation, which increase the risk of late neurotoxicity. The aim of this phase II trial was to investigate whether chemotherapy alone could induce durable remissions. Thirty non-immunocompromised patients were enrolled in two treatment groups, according to age. Patients in group A (< 65 years; n = 17) received carmustine, vincristine, dexamethasone, high-dose methotrexate and high-dose cytarabine. Patients in group B > 65 years: n = 13) were treated with carmustine, vincristine, dexamethasone and high-dose cytarabine. Both groups received intrathecal treatment. Radiotherapy was reserved for patients with stable or progressive disease. The overall response rate in group A was 65% (complete response 35%; partial response 29%) and in group B. 61% (complete response 23%; partial response 38%), but only 6 remissions were maintained without irradiation. In all, there were five treatment-related deaths. Responses were induced, but were mostly of short duration, and the treatment was associated with profound toxicity.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Central Nervous System Neoplasms; Cytarabine; Dexamethasone; Female; Follow-Up Studies; Humans; Injections, Spinal; Leucovorin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Male; Middle Aged; Pilot Projects; Radiotherapy, Adjuvant; Vincristine

Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone.. Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity.. The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting.. The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cytarabine; Dexamethasone; Drug Administration Schedule; Eye Neoplasms; Female; Humans; Leucovorin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Pilot Projects; Thiotepa; Vincristine

Seventy-three patients with Stage III abdominal non-Hodgkin's lymphoma were prospectively treated following two sequential protocols (P): L278 P (group A, 33 patients) (1978-1983) and L384 P (group B, 40 patients), (1984-1991). No patient received radiotherapy. The L278 P included 7 drugs: cyclophosphamide, vincristine (VCR), adriamycin (ADR), prednisone, methotrexate (MTX), dexamethasone, and 6-mercaptopurine, given for remission induction, maintenance, and CNS prophylaxis. In the L384 P we introduced a consolidation phase consisting of intravenous MTX and citrovorum factor rescue, and IV cytosine arabinoside. VCR was also added to the monthly doses and the maintenance phase was reduced from 18 to 15 months. From January 1988 we changed ADR for epirubicin in the same doses. Prophylactic treatment of the CNS, in the L384 P, was intensified by increasing the number of doses of MTX IT in the remission, induction, and consolidation phases, and with the use of ara-C IT. Laparotomy in 50 patients allowed partial resection in 16, and second-look laparotomy was performed in 27 patients. Viable tumor was found in four patients. Three patients (G-A) died from metabolic complications and another 4 (2 G-A and 2 G-B) failed to attain CR and died. A total of 28 (85%) of 33 children of G-A and 38 (95%) of 40 children in G-B achieved CR. Five children died in remission (2 G-A, 3 G-B). Three patients (G-A) relapsed in the CNS and one (G-B) relapsed in the abdomen and died. Disease-free survival at 120 months was 70% in G-A and 84% in G-B.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Child, Preschool; Costa Rica; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Female; Humans; Infusions, Intravenous; Leucovorin; Life Tables; Lymphatic Metastasis; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Prospective Studies; Remission Induction; Survival Rate; Vincristine

The therapeutic response to high-dose methotrexate (HD-MTX) therapy for primary central nervous system lymphoma (PCNSL) varies. Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. MTX incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. We hypothesized that the extent of polyglutamylation in tumor cells determines treatment resistance. Here, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status. Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma lines were used for in vitro experiments, and folpolyglutamate synthetase (FPGS), which induces polyglutamylation, was knocked down with short-hairpin RNA, and a stable cell line with a low rate of polyglutamylation was established. Cell viability after MTX treatment with LV rescue was evaluated using sodium butyrate (NaBu), a histone-deacetylase inhibitor that induces polyglutamylation by elevating FPGS expression. The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). In vitro, the relief effect of LV after MTX administration was significantly enhanced after FPGS knockdown in al cell lines, whereas enhancement of FPGS expression by NaBu treatment significantly reduced this relief effect. These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combination therapy with HD-MTX and polyglutamylation-inducing agents might represent a promising strategy for PCNSL treatment.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Survival; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Treatment Outcome; Vitamin B Complex

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/μL and blasts with/without ≥ 10 RBCs/μL or ≥ 5 WBCs/μL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/μL plus blasts with/without ≥ 10 RBCs/μL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Cerebrospinal Fluid; Child; Clinical Trials as Topic; Cranial Irradiation; Dexamethasone; Disease-Free Survival; Erythrocyte Count; Female; Humans; Leucovorin; Leukocyte Count; Male; Methotrexate; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Neoplasms; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Demyelinating Diseases; Diagnosis, Differential; Doxorubicin; Encephalomyelitis, Acute Disseminated; Etoposide; Humans; Hydrocortisone; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Magnetic Resonance Imaging; Male; Methotrexate; Prednisone; Vincristine

High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.. Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations (MTX) were collected. Delayed plasma excretion was defined as (MTX) ≥1 μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until (MTX) <0.1 μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.. Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m² (41.1 CV %) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (P < 0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.. Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than 1 year may need additional monitoring to avoid toxicity.

Topics: Antimetabolites, Antineoplastic; Ascitic Fluid; Central Nervous System Neoplasms; Child, Preschool; Cohort Studies; Combined Modality Therapy; Down-Regulation; Drainage; Female; Humans; Infant; Infant, Newborn; Leucovorin; Male; Metabolic Clearance Rate; Methotrexate; Neuroprotective Agents; Pericardial Effusion; Pleural Effusion, Malignant; Postoperative Complications; Retrospective Studies; Subdural Effusion

Topics: Antimetabolites, Antineoplastic; Central Nervous System Neoplasms; Female; Humans; Leucovorin; Male; Methotrexate; Neuroprotective Agents; Postoperative Complications; Subdural Effusion

Topics: Antimetabolites, Antineoplastic; Central Nervous System Neoplasms; Female; Humans; Leucovorin; Male; Methotrexate; Neuroprotective Agents; Postoperative Complications; Subdural Effusion

We assessed the outcome of high-dose methotrexate (HD-MTX) chemotherapy with or without radiotherapy (RT) in primary central nervous system lymphoma (PCNSL) patients.. Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2) MTX with Leucovorin rescue and 1.4 mg/m(2) vincristine (day two), which was administered every other week for 6 weeks. Only the patients who were younger than 60 years received RT. All patients received two cycles of 3000 mg/m(2) cytarabine at the end of the treatment for two successive days.. Diffuse large B-cell lymphoma was the most common histologic subtype (90.2%), and twenty-six (51.0%)patients had multiple brain lesions. The median survival of patients who were younger than 60 years was 37 months. For patients who were older than 60 years, the median survival was 20 months. The median survival of men and women were 30 and 34 months, respectively. There was no significant difference in survival of patients in terms of age and sex. Overall, sixteen patients (31%) out of fifty-one patients died, five of them were older than 60 years and eleven were younger than 60 years. Twenty-five (49%) of all patients experienced relapse, and 10 (40%) of them died after rechemotherapy.. The base of our chemotherapy regimen was HD-MTX as the regular doses of MTX cannot penetrate the blood brain barrier (BBB). Our results indicated that the combination of HD-MTX with RT may not influence the outcome of PCNSL; thus, RT cannot be the first line therapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Central Nervous System Neoplasms; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Radiotherapy, Adjuvant; Retrospective Studies; Vincristine

Central nervous system (CNS) relapse continues to be a frequent and usually fatal complication in patients with diffuse large B cell lymphoma (DLBCL). Multiple factors identify the possibility of relapse and justify neurological prophylaxis; however, most of these have not been confirmed. Thus, the use of prophylaxis has not been defined. From 1988 to 2008, 3,258 patients with DLBCL with higher clinical risks and multiple extranodal involvement that have been treated with standard anthracycline-based chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-R (CHOP plus rituximab) and that achieve complete response were retrospectively analyzed to assess the efficacy of CNS prophylaxis. One thousand five patients received different schedules for CNS prophylaxis, and 2,253 patients did not receive CNS prophylaxis. CNS relapse was similar in patients who receive prophylaxis (6 %) compared to patients who did not receive prophylaxis (5.9 %). Overall survival of patients who either receive or did not receive prophylaxis was not statistically significant: 49 % versus 53 % (p = 0.802). Thus, it seems that CNS prophylaxis did not improve outcome in this special setting of patients, and no prognostic factors to predict the presence of CNS relapse were identified. It is evident that multicentric studies are necessary to define the role of prophylaxis in order to prevent CNS relapse and that the therapeutic procedure will be carefully revised.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Care Facilities; Central Nervous System Neoplasms; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Humans; Hydrocortisone; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged

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

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Hydrocortisone; Infant; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Prednisone; Recurrence; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Vincristine

Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found.. One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy.. The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4 +/- 4.8% [95% confidence intervals (CI)] and 30.2 +/- 4.8% (95% CI), respectively. The ProMACE-MOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20-30 Gy WB, and 500 mg/m(2) of MTX dose appeared important determinants of OS.. A modest dose of MTX (500 mg/m(2)) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Chemotherapy, Adjuvant; Cognition; Cranial Irradiation; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Leucovorin; Lymphoma; Male; Mechlorethamine; Methotrexate; Middle Aged; Neoplasm Staging; Prednisone; Procarbazine; Radiotherapy, Adjuvant; Retrospective Studies; Salvage Therapy; Treatment Outcome; Vincristine

Anaplastic large cell lymphoma (ALCL) is 1 of 17 mature T cell neoplasms described by the World Health Organization. Primary central nervous system (PCNS) ALCL represents a distinct rare form of this family of non-Hodgkin lymphoma and discussions of prognosis and management are limited to case reports and case series. Therapies for this disease largely parallel that of other PCNS lymphomas. We report the case of a 38-year-old male soldier who presented with a parieto-occipital mass lesion and neurological sequelae without evidence of systemic disease. Pathologic evaluation of tissue from brain biopsy confirmed ALCL. We elected treatment with an intensive combination of systemic and intrathecal chemotherapy with radiotherapy. Our patient is in complete remission 15 months following therapy. Tailored therapies for PCNS ALCL are unavailable and this regimen may be an option for patients who can tolerate intensive treatments.

Topics: Adult; Antineoplastic Agents; Central Nervous System Neoplasms; Combined Modality Therapy; Dexamethasone; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Procarbazine; Vincristine

Topics: Central Nervous System; Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Humans; Leucovorin; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Recurrence; Risk

Primary central nervous system lymphoma (PCNSL) is a lymphoma arising within the brain or spinal cord in the absence of evident localisation outside the central nervous system (CNS). Poor results in the management of relapsed PCNSL justify the need for vigorous initial therapeutic regimens, and chemotherapy should not be reserved for recurrent disease. Chemotherapy (MBACOD scheme) was delivered prior to irradiation in a group of 20 PCNSL patients, another 8 PCNSL patients underwent radiotherapy only, and the overall survival was evaluated. Computed tomography (CT) images in the group of patients treated with chemotherapy, showed there to be 70% complete responders (CR), 15% non-responders (NR) and 15% partial responders (PR). Half of the CR were scheduled for radiotherapy only at tumour recurrence. The median disease-free period and survival time of the whole group treated with early chemotherapy followed by radiotherapy were 24 and 32 months, respectively, but in the subgroup of CR (70%), taking into account also the patients not yet receiving radiotherapy, these were 38 and 48 months, respectively. The disease-free and survival times in the group of CR (75%) of patients treated with radiotherapy only were 13 and 18 months, respectively. At tumour recurrence, CR to chemotherapy had a second disease-free period longer than 2 years after radiotherapy. Our data support the belief that in scheduling the treatment of PCNSL after histological diagnosis, the first step is to devise high-dose chemotherapy with drugs able to cross an intact blood-brain barrier. The results of our primary approach with early chemotherapy in PCNSL support a consensus to continue chemotherapy until tumour recurrence, and only at that event to initiate radiotherapy. It is a challenge and an option worthy of continuing investigation.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Neoplasms; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Magnetic Resonance Imaging; Methotrexate; Middle Aged; Tomography, X-Ray Computed; Vincristine

The treatment of patients with primary non-Hodgkin's lymphoma of the central nervous system (PCNSL) is still of limited success, as compared with other extranodal sites. The poor results obtained with radiotherapy alone can be improved by adding chemotherapy reaching a median survival up to over 30 months and 5-years-survival rate up to 35%. The optimal management for patients with CNS relapse of systemic lymphoma remains uncertain and their prognosis is even worse. Here, we describe our preliminary data on the treatment of patients with CNS lymphoma with a new regimen composed of CNS-penetrating drugs, namely: carmustine (BCNU) 80 mg/m2 i.v. dl, methotrexate 1500 mg/m2 over 24h i.v. d2, procarbacine 100 mg/m2 p.o. d1-8, and dexamethasone 3 x 8 mg p.o. d1-14. An average of 3 treatment courses were given under response control seen using CT-scan or NMR. Patients with positive CSF cytology received additionally intrathecal therapy with methotrexate. Until now between March 1994 and September 1997, 7 patients with PCNSL and 4 patients with CNS relapse of systemic lymphoma have been treated. The median age of the patients was 56 (range, 39-74); 5 patients were > or =60 years old. Three patients had multifocal disease. Whole brain radiotherapy with 4000 to 5000 cGy was given in 7 patients (cerebrospinal in 1 patient). Complete response at the end of chemotherapy was achieved in 6 patients, and a partial response in two. Most remarkably, 2 elderly patients (70 and 57 years), 1 patient with multifocal disease and 1 with simultaneous CNS and systemic relapse after chemotherapy had a complete remission lasting for 40 months, and a partial remission lasting for 37 months, respectively.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Carmustine; Central Nervous System Neoplasms; Combined Modality Therapy; Dexamethasone; Female; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Procarbazine; Radiography; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Neoplasms; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Leucovorin; Lymphoma; Methotrexate; Middle Aged; Vincristine

Disease-free survival in primary CNS lymphoma has improved with the advent of methotrexate-based pre-irradiation chemotherapy. Prolonged response durations have been noted in six of eight patients refusing radiation therapy in two of our prior series. We have treated an additional 11 patients with methotrexate-based chemotherapy without subsequent planned irradiation. Some received maintenance chemotherapy. Most have had durable responses with little or no toxicity. Prolonged responses can be maintained without radiation therapy, thus avoiding potential long-term radiation toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cranial Irradiation; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Treatment Outcome; Vincristine

The treatment of primary central nervous system lymphoma with chemotherapy prior to whole-brain radiation therapy (WBRT) has improved outcome considerably in this previously fatal disease. Complete or partial responses to intravenous methotrexate (3.5 gm/sq m with leucovorin rescue every 3 weeks for two to four cycles) were seen in 12 of 13 patients originally treated. A total of 25 patients (including the original 13) have now been treated with one to six cycles of methotrexate every 10 to 21 days prior to WBRT. Twenty-two had partial or complete responses, with a median duration of response of 32 months. Median survival time was 33 months (42.5 months in those responding to therapy). Nine patients are alive and without evidence of disease 9 to 122 months following therapy. Acute and long-term toxicities were minimal. Systemic methotrexate administration prior to WBRT is well tolerated and produces long-term survival.

Topics: Adult; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Combined Modality Therapy; Cranial Irradiation; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy Dosage; Remission Induction; Survival Rate; Treatment Outcome

High response and overall survival rates have been reported for second- and third-generation combination chemotherapy regimens used in the treatment of advanced intermediate- and high-grade non-Hodgkin's lymphoma (NHL). Results with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy have been particularly impressive, although this regimen produces considerable toxicity. We have devised a similar regimen, which differs from previously reported weekly regimens in that it includes etoposide given at 14-day intervals. The doses of methotrexate and prednisolone were lower in our regimen than those used in MACOP-B. Alternating cycles of cyclophosphamide, doxorubicin, and etoposide (week 1) and methotrexate, bleomycin, and vincristine (week 2) were given for a total of 12 weeks, with continuous oral prednisolone and prophylactic antibiotics. We report here the first 61 patients entered onto this study. The overall response rate is 84% (57% complete remission [CR], 27% partial remission [PR]). With a median follow-up of 32 months for surviving patients, the actuarial overall survival at 3 years is 47%, and the failure-free survival is 45%. The dose-limiting toxicity of this regimen was mucositis. Five deaths occurred during chemotherapy, two of which were due to sepsis. The dose intensities of cyclophosphamide and doxorubicin in this regimen are considerably lower than those in MACOP-B. However, because of the inclusion of etoposide, the projected average relative dose intensity for our regimen is higher than that for MACOP-B. Our regimen has produced inferior results to those reported for MACOP-B. This may be because the addition of etoposide has failed to compensate for the lower doses of doxorubicin and cyclophosphamide. Alternatively, it may reflect differences in the presenting features of the patient populations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prednisone; Survival Analysis; Vincristine

In a random HIV-seropositive population, malignant lymphomas were diagnosed in 31 patients, of whom 24 (77%) had non-Hodgkin lymphoma (NHL) and 7 (23%) Hodgkin lymphoma (HL). The prevalence of NHL among AIDS patients was 8% (23/279 cases), with a prevalence of 17% among autopsied patients (16/96 cases). No patient with HL had AIDS at the time of diagnosis. In 7 of 23 AIDS patients with NHL (30%) the diagnosis was made only post mortem; among these were all 5 patients with primary CNS NHL. Median survival from the time of diagnosis was 1 month for patients with NHL and 3 months for those with HL. In individual patients, survival for several years may be possible with chemotherapy. Certain patients with NHL appear to benefit from intensive chemotherapy with a combination of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOPB protocol). Appropriate, therapeutic strategies taking into account the patients' individual conditions, including the overall prognosis, urgently requires development. Metastatic CNS involvement, which was the primary cause of death in 5 of 11 patients with NHL (45%) receiving chemotherapy, represents a serious limitation to successful treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Neoplasms; Cyclophosphamide; Doxorubicin; Female; HIV Seropositivity; Hodgkin Disease; Humans; Leucovorin; Lymphoma; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Prednisone; Prognosis; Vincristine