levoleucovorin and Brain-Neoplasms

To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.. ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.. Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.. Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Oxaliplatin

The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial.. To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX.. The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009.. Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study.. Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status.. Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03).. The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy.. clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; DNA Mutational Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Treatment Outcome

Gestational trophoblastic disease is a fascinating group of pregnancy disorders characterised by abnormal proliferation of trophoblast, ranging from benign to malignant. Because the disease is uncommon, there is a need to formulate management with the assistance of collective information.. A review of available information from English written literature was undertaken, especially data reported by registries around the world (Charing Cross Hospital in England, the North-western University and the New England area in the USA as well as our own experience in Queensland, Australia). Where possible, collated data from relevant studies were analysed to answer some of the questions posed in clinical practice, with reference to metastatic disease to liver and brain, twinning of molar gestation and coexisting fetus, and placental-site tumour.. We found that molar gestation can be classified according to its clinical presentation which influences the time taken to reach human chorionic gonadotropin (HCG) 'negativity' and the risk of persisting disease. Categorisation of risk is the basis for choice of chemotherapy to achieve good outcomes. Metastases to liver and brain remain problems in management; the development of 'new' metastases during chemotherapy is a very poor prognostic factor. In the variant of twinning with molar gestation and coexisting fetus, it is important to elucidate the fetal karyotype in planning management: a 69XXX fetus is not salvageable but a normal 46XX or 46XY fetus faces the prospect of early preterm delivery. The placental-site tumour is very rare; localised disease is curable by surgery; chemotherapy is less effective in disseminated disease. From collated worldwide data, the recurrence rate after one mole is 1.3% and after two or more is 20%. Reproductive outcome in subsequent pregnancies, even after multidrug chemotherapy, is not different from the general population. Because of the increased risk long-term of second tumours after multidrug chemotherapy a closer surveillance of these patients is necessary.. In general, the disease in its persisting or malignant form is 'a cancer model par excellence' because of an identifiable precursor condition, a reliable HCG marker, and sensitivity of the disease to cytotoxic drugs. With current management, retention of fertility is possible and normal reproductive outcome assured.

Topics: Brain Neoplasms; Female; Gestational Trophoblastic Disease; Humans; Hydatidiform Mole; Leucovorin; Liver Neoplasms; Methotrexate; Neoplasms, Second Primary; Pregnancy; Queensland; Recurrence; Registries

Gestational trophoblastic diseases comprise a rare spectrum of disorders in which the normal regulatory mechanisms controlling the behaviour of trophoblastic tissue are lost. They vary from the benign complete and partial hydatidiform moles to the frankly malignant choriocarcinoma and placental site trophoblastic tumours. The majority will be cured by suction curettage, followed by human chorionic gonadotrophin screening, but some will go on to need chemotherapy. The majority of patients will be cured even despite the presence of metastatic disease. Patients should have their treatment stratified according to various prognostic factors in order to ensure firstly their disease is eliminated and secondly to reduce the incidence of long-term treatment complications.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cyclophosphamide; Dactinomycin; Drug Administration Schedule; Etoposide; Female; Humans; Leucovorin; Methotrexate; Neoplasm Staging; Pregnancy; Prognosis; Trophoblastic Neoplasms; Uterine Neoplasms; Vincristine

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Boston; Brain Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Dexamethasone; Doxorubicin; Eye Neoplasms; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Meningeal Neoplasms; Methotrexate; Prednisone; Radiotherapy, Adjuvant; Remission Induction; Time Factors; Treatment Outcome; Vincristine

To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer.. The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2).. All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients.. The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome

To determine whether a lower dose of hyperfractionated whole brain radiation reduces central nervous system morbidity without compromising survival for primary CNS lymphoma (PCNSL) patients receiving combined modality treatment.. One hundred and two patients received a course of pre-radiation chemotherapy, followed by whole brain radiation, followed by cytosine-arabinoside. Initial radiation dose was 45 Gy/25 fractions (RT) then the study was amended to reduce this dose for complete responders to induction chemotherapy to 36 Gy/30 fractions/3 weeks (HFX). Eighty-two patients received radiotherapy and were evaluable for toxicity analysis (66 RT patients and 16 HFX patients). MMSE scores and survival for the 40 patients who received radiotherapy after complete response to chemotherapy (27 RT and 13 HFX) were compared. There were no notable differences in pre-treatment patient characteristics between the RT and HFX groups.. Neurotoxicity: By 4 years, there were 8/82 (10%) grade 5 neurotoxicities which included 2/16 (13%) grade 5 encephalopathies and 0/27 in the RT group of complete responders to chemotherapy. Survival: There was no statistically significant difference in overall or progression-free survival (PFS) between the chemotherapy-complete responders who received RT and HFX. Cognitive function testing: MMSE scores improved at 8 months across both treatment groups. Analysis of the area under the MMSE curve at 8 months showed no statistically significant difference between RT and HFX groups (P=0.81). Leukoencephalopathy occurred later in the HFX group than in the RT patients.. Although the HFX schedule represented a 25% reduction in biologically effective tumor dose in comparison, PFS and overall survival were not significantly affected. The HFX regimen delayed but did not eliminate severe neurotoxicity from chemoradiation in PCNSL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Cognition; Combined Modality Therapy; Disease Progression; Dose Fractionation, Radiation; Humans; Leucovorin; Lymphoma; Methotrexate; Procarbazine; Radiation Injuries; Survival Rate; Vincristine

The purpose of this prospective trial was to study a combined-modality treatment including local consolidation by surgery or radiotherapy and high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell (PBSC) transplantation. In all, 48 patients with oligometastatic breast cancer amenable to local treatment after induction chemotherapy with epirubicin and cyclophosphamide or paclitaxel and cisplatin, depending on prior adjuvant chemotherapy, were enrolled. The median follow-up was 41 months (range, 7-85 months). PBSC were collected in 47 patients, and 40 received one or two courses of HDC. Local therapy was given in 37 patients. No treatment-related deaths occurred. Of 47 evaluable patients, 36 (75% of intention-to-treat population) had no evidence of disease or complete remission after completion of therapy. Six patients (12.5%) had partial response, two patients (4%) no change, and three patients (6%) progressive disease. The median time to progression and overall survival was 17.5 (95% confidence interval (CI), 14-21 months) and 42.2 months (95% CI, 33-52 months), respectively, and 27% of patients were progression free after 5 years. In conclusion, patients with oligometastatic breast cancer can be treated safely with this combined modality protocol with promising relapse-free survivals.

Topics: Adult; Antimetabolites, Antineoplastic; Brain Neoplasms; Breast Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Middle Aged; Pilot Projects; Prospective Studies; Remission Induction; Survival Rate; Transplantation, Autologous

To assess the efficacy and toxicity of combined modality therapy with short intensive primary chemotherapy in the treatment of primary CNS lymphoma (PCL).. Prospective study of 31 nonimmunodeficient patients with PCL treated with initial chemotherapy (13 shortened MACOP-B; and 18 modified MACOP with high dose methotrexate) followed by radiotherapy (whole brain and a boost). Patients were aged 18-72 years (median 51 years). Eight patients had positive CSF cytology of which one had spinal meningeal disease; one patient had vitreous involvement.. The overall complete response (CR) rate after chemotherapy and radiotherapy was 69% (95% Confidence Interval: 49-84%). At a median follow-up of 24 months (4 months to 10 years) median survival was 23 months and 5-year survival 34%. Age, sex, performance status, number of lesions, CSF cytology, and extent of surgery were not of prognostic significance for survival on univariate analysis. Eleven patients developed mucositis (Grade 3+) and 21 hematological toxicity (Grade 3+) with 22 septicemic episodes in 15 patients. Three patients developed dementia, one assumed to be treatment related, and two due to recurrent disease.. The survival results of short intensive primary chemotherapy followed by radiotherapy are similar to the results of chemotherapy in Stage IV aggressive systemic non-Hodgkin's lymphoma, although the treatment was associated with high morbidity. The apparently favorable results when compared to radiotherapy alone may at least in part be due to selection of patients with good prognostic factors. To confirm the benefit of combined chemotherapy and radiotherapy over either of the two modalities alone requires evaluation in large prospective and ideally randomized studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Leucovorin; Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Male; Methotrexate; Middle Aged; Prednisone; Prospective Studies; Vincristine

From December 1995 to July 1997, six patients with primary malignant lymphoma in the central nervous system were treated with 2 to 5 cycles of the M-CHOP regimen (methotrexate 3 g/m2 on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and predonisolone 60 mg on day 1 to 14: folic acid was given 3 hours after methotrexate at 10 mg/m2 every 3 hours for 9 doses intravenously). Five patients achieved complete remission (CR) and one experienced partial remission (PR). Posttherapeutic studies were performed in all patients with an average follow-up period of 20.1 months (range 8.1-26.8 months) after confirming the diagnosis. There was no evidence of recurrence of the tumors or growth of residual tumors in any of the patients in this period. The major toxic effect was myelosupression with leukopenia. Alopecia was observed in all patients. No treatment-related deaths were observed. The M-CHOP regimen seems to be a promising treatment for primary malignant lymphoma in the central nervous system.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Prednisone; Remission Induction; Vincristine

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Etoposide; Humans; Leucovorin; Medulloblastoma; Methotrexate; Mitolactol; Procarbazine

Brain metastases represent a common complication of breast and lung cancer, with an overall incidence exceeding 30-40% of cases. Results achieved with radiotherapy are disappointing, with a median survival of a few months, and no clear activity has been observed with chemotherapy. The aims of this study were to assess the activity and feasibility of a new chemotherapeutic approach according to the following schedule: lomustine, 80 mg/m2 day 1; carboplatin, 80 mg/m2 days 1, 8, 15, 22; vinorelbine, 20 mg/m2 days 1, 8, 15, 22; L-leucovorin 250 mg/m2 days 1, 8, 15, 22; and fluorouracil, 500 mg/m2 days 1, 8, 15, 22. Cycles were repeated every 6 weeks. Since January 1994, 28 patients have been enrolled and 26 are evaluable for response and side effects. Major patient characteristics were median age, 55 years (range 31-72); men/women 15/11; lung primary, 20; breast primary, 6; performance status Eastern Cooperative Oncology Group, 0-2. A total of 64 cycles were administered (median/patient, two cycles). Nine partial remissions have been observed (35%, 95% confidence interval 17-56%), 6 disease stabilizations, and 11 disease progressions. Median duration of response was 3 months, and median time to progression for the whole group was 3.7 months (range 1-7). Treatment was well tolerated. Mild or moderate side effects included neutropenia, thrombocytopenia, mucositis, and nausea/vomiting; grade III-IV toxicity included neutropenia and thrombocytopenia. In conclusion, our results indicate that the schedule proposed is feasible and effective in this subset of patients.

Topics: Adenocarcinoma; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carboplatin; Female; Fluorouracil; Humans; Leucovorin; Lomustine; Lung Neoplasms; Male; Middle Aged; Remission Induction; Survival Analysis; Vinblastine; Vinorelbine

Thirty patients with recurrent primary brain tumors were treated with a combination of 5-fluorouracil and leucovorin. There were three responses seen. Toxicity consisted of stomatitis, diarrhea, and hematological suppression. 5-fluorouracil and leucovorin would appear to be minimally effective in recurrent brain tumors.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Astrocytoma; Brain Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Oligodendroglioma; Recurrence; Stomatitis; Thrombocytopenia

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Recurrence; Survival Analysis; Vincristine

Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.

Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Female; Fluorouracil; Glioblastoma; Glioma; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged

Non-Hodgkin's lymphoma of the central nervous system (NHL-CNS) is thought to account for about 1% of primary brain tumours. Radiation therapy has mainly been applied to treat cerebral lymphoma, but the low cure rate and the lack of enduring response have stimulated the search for alternatives. With the aim of postponing radiotherapy as long as possible, we tested the efficacy of a M-BACOD schedule administered immediately after histological diagnosis in 14 patients. After two M-BACOD courses 10 (71%) patients displayed an objective response (i.e. were apparently tumour-free when examined by CT). In 6 (60%) M-BACOD-responsive patients, radiotherapy was delayed for 5 months (without recurrences after a follow-up ranging from 9 to 18 months). Moreover, in 3 M-BACOD-responsive patients, no recurrence took place (even without radiotherapy) after a follow-up of 6-12 months. We conclude that radiation can be postponed after chemotherapy or delayed until tumor recurrence.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Remission Induction; Time Factors; Treatment Outcome; Vincristine

Thirty-three patients with ALL/AUL in first relapse were treated with an induction of prednisone, vindesine, daunorubicin, Erwinia asparaginase, i.t. MTX (phase I), high-dose cytarabine, and etoposide (phase II). Twenty-one (64%) achieved a complete remission, one a partial remission. Side effects of induction-phase I were predominantly hematological with subsequent infections and gastrointestinal toxicity. In phase II some patients had additional cutaneous, ocular, and hepatic toxicity. The treatment efficiently induced remissions with tolerable toxicity in relapsed ALL. The disease-free survival, however, needs to be improved.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Brain Neoplasms; Combined Modality Therapy; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Germany, West; Humans; Ifosfamide; Leucovorin; Life Tables; Male; Methotrexate; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Spinal Cord Neoplasms; Teniposide; Testicular Neoplasms; Vindesine

Twenty-five patients with CNS metastases of choriocarcinoma were treated with a regimen incorporating etoposide, methotrexate, and actinomycin (EMA) alternating weekly with vincristine and cyclophosphamide (CO). The dose of methotrexate was increased to 1 g/m2. Eighteen patients presented with CNS metastases, or developed them on inappropriate treatment started elsewhere. Following EMA/CO chemotherapy, three patients died within the first 3 weeks, one is alive with active disease, one died with drug resistance, and 13 (72%) patients are surviving disease-free. Two of seven patients (29%) who developed CNS metastases on treatment with EMA/CO or relapsed after EMA/CO are disease-free after additional chemotherapy and surgery. The contribution toward survival of the craniotomy in six of 18 patients treated initially or early with EMA/CO remains unclear, but was crucial to those patients with drug resistance.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Choriocarcinoma; Chorionic Gonadotropin; Clinical Trials as Topic; Craniotomy; Dactinomycin; Doxorubicin; Etoposide; Female; Humans; Leucovorin; Methotrexate; Middle Aged; Prognosis; Vincristine

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Small Cell; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Radiotherapy Dosage; Vincristine; Whole-Body Irradiation

A randomized trial of combined modality therapy employing combination chemotherapy (cyclophosphamide (CTX) and methotrexate (MTX), CTX, MTX and Vincristine (VCR) and CTX, VCR and high-dose MTX with citrovorum rescue) and radiation therapy was compared to cyclophosphamide and radiation therapy in 258 patients with pulmonary small cell carcinoma. Patients were also rendomized: 1) to determine the effects of prophylactic whole brain irradiation; and 2) to establish the effects of maintenance chemotherapy. Survival, frequency of response and site of relapse were different in patients with limited disease (LD) (disease confined to lung, mediastinum and supraclavicular lymph nodes) when compared with disease spread beyond these sites (extensive disease) (ED). No survival advantage was seen in LD when combination chemotherapy was employed, although the frequency of complete remission was greater with three drugs than with one or two drugs (40% vs. 32%). In ED frequency of response was greater for three drugs than for one and two drugs (60% vs. 40%), but there was no survival advantage. The median survival time for complete responders was similar for limited or extensive disease (12.1 months), but 23.8% were alive at 24 months with LD compared to none with ED. Maintenance chemotherapy significantly prolonged survival by 16.8 months with 33% alive at 24 months compared to 9% who were unmaintained. Prophylactic while brain irradiation prevented brain metastases with only 4% developing this complication as compared to 18% of control subjects, but did not influence survival.

Topics: Antineoplastic Agents; Brain Neoplasms; Carcinoma, Small Cell; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Random Allocation; Remission, Spontaneous; Time Factors; Vincristine

Prophylactic antibiotics decrease mortality and morbidity in patients with hematological malignancies following intensive chemotherapy. However, the efficacy of prophylactic antibiotics for pediatric patients with solid tumors remains unclear.. We retrospectively assessed 103 neutropenic periods from 26 patients with neuroblastoma or brain tumors following three different intensity chemotherapy regimens (05A3, A, and B). While piperacillin was intravenously administered as prophylaxis (PIPC prophylaxis group), the historical control group received no prophylaxis. As patients exhibited a variable degree of myelosuppression based on the intensity of the chemotherapy regimen, we separately evaluated the frequency and severity of febrile neutropenia (FN) in each regimen.. Following intensive chemotherapy, we observed a significantly lower frequency of FN in the PIPC prophylaxis group compared with the historical control group in both regimen 05A3 (20% vs 65%; P = 0.01) and regimen A (56% vs 93%; P = 0.02). We also observed a shorter duration of fever, lower maximum fever, and lower C-reactive protein levels in the PIPC prophylaxis group compared with the historical control group after regimens 05A3 and A. Conversely, the frequency and severity of FN were not different between the two groups after moderate-intensity chemotherapy (regimen B). However, a longitudinal routine surveillance study of Pseudomonas aeruginosa also indicated a reduction in the susceptibility to PIPC throughout the study period.. Although PIPC prophylaxis might provide an advantage for severe neutropenia in pediatric patients with solid tumors, there is concern regarding bacterial resistance to antibiotics. Therefore, further careful examination is necessary for adaptation.

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Child; Child, Preschool; Drug Resistance, Microbial; Female; Fever; Fluorouracil; Humans; Infant; Leucovorin; Male; Methotrexate; Neuroblastoma; Neutropenia; Piperacillin; Retrospective Studies

Treatment options for locally advanced rectal cancer have continued to consist largely of chemotherapy, chemoradiation, and/or surgical resection. For patients who are unable to undergo these therapeutic modalities or who do not to experience a response to them, treatment options are limited. We report 3 cases of mismatch repair-deficient (dMMR) locally advanced adenocarcinoma of the rectum that showed significant response with neoadjuvant immunotherapy-based systemic treatment. The first patient was not eligible for standard therapy because of a history of radiotherapy to the prostate with concurrent comorbidities and therefore received single-agent pembrolizumab. The second patient did not respond to total neoadjuvant chemoradiation and subsequently received combined nivolumab and ipilimumab. The third patient had a known family history of Lynch syndrome and presented with locally advanced rectal cancer and a baseline carcinoembryonic antigen level of 1,566 ng/mL. She was treated using neoadjuvant pembrolizumab and FOLFOX (folinic acid, fluorouracil, oxaliplatin). In this small series, we suggest that single-agent and combined-modality neoadjuvant immunotherapy/chemotherapy appear to be safe and effective treatment options for patients with (dMMR) locally advanced rectal cancer. Our findings encourage further studies to investigate the role of neoadjuvant immunotherapy as a viable treatment strategy in this population.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Immunotherapy; Ipilimumab; Leucovorin; Male; Neoadjuvant Therapy; Neoplastic Syndromes, Hereditary; Nivolumab; Organoplatinum Compounds; Rectal Neoplasms

We present the case of a 55-year-old male patient who presented with palpable cervical lymphadenopathy. Excisional biopsy showed metastatic adenocarcinoma of unknown origin. Imaging showed a bladder mass following which he underwent transurethral resection of bladder tumour. Histopathological evaluation of mass confirmed a poorly differentiated adenocarcinoma with signet-ring cell features. Immunohistochemistry was suggestive of metastatic urachal cancer. He agreed for enrollment in a clinical trial, however soon after 1st cycle, he developed immune pneumonitis requiring high dose steroids. On follow-up, MRI brain was done for evaluation of headache which showed metastatic intracranial disease. He completed radiotherapy following which he was started on FOLFOX chemo regimen (folinic acid, 5-fluorouracil and oxaliplatin).

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Brain Neoplasms; Diagnosis, Differential; Fluorouracil; Humans; Immunohistochemistry; Immunosuppressive Agents; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Neck; Neoplasm Staging; Organoplatinum Compounds; Radiotherapy; Urinary Bladder Neoplasms

To evaluate the pattern of tumor relapse of pathological complete response (pCR) patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), and to identify predictive factors of distant metastasis in pCR patients after nCRT.. This was a retrospective analysis of 118 LARC patients who achieved a pCR following nCRT and TME from 2008 to 2015. Clinicopathological and therapeutic parameters were evaluated as possible predictors of distant metastasis-free survival (DMFS), and COX regression analysis was performed.. After a median follow-up of 57 months, the 5-year overall and disease-free survival rates were 94.7% and 88.1%, respectively. Overall, 6 patients (5.1%) died, no local recurrence occurred, 13 patients (11%) developed distant metastases, including lung (n = 5), liver (n = 2), bone (n = 3), lung and brain (n = 1), peritoneal (n = 1), and spleen (n = 1) metastasis. On univariate analysis, tumor distance from the anal verge (HR = 0.706, P = 0.039), acellular mucin pools (HR = 6.687, P = 0.002), and MUC1 expression (HR = 8.280, P < 0.001) were independently associated with DMFS. COX regression demonstrated that MUC1 expression (HR = 3.812, P = 0.041) remained to be an independent predictor of DMFS in pCR patients.. Distant metastasis still remained a major concern in pCR patients following nCRT and TME. Tumor distance from the anal verge, acellular mucin pools, and MUC1 expression were associated with distant metastasis in patients with pCR. MUC1 staining remained to be an independent risk factor for DMFS. Such information could facilitate treatment decision in these patients, such as adjuvant chemotherapy and follow-up.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Incidence; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Mesentery; Middle Aged; Mucin-1; Mucins; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Proctectomy; Proportional Hazards Models; Rectal Neoplasms; Remission Induction; Retrospective Studies; Splenic Neoplasms

Topics: Brain Neoplasms; Combined Modality Therapy; Humans; Leucovorin; Lymphoma; Methotrexate; Treatment Outcome

Ependymomas represent 10% of pediatric brain tumors. In the recent WHO 2016 classification, pathology is enriched by localization and molecular biology. Whatever the age, total removal by one or several looks when required remains a major prognostic factor. In children, focal radiation remains a standard, while the role of chemotherapy is matter of randomized studies. In infants, front line chemotherapy is the standard. Inclusion in the SIOP ependymoma II protocol is encouraged. In case of relapse, further surgery and radiation are advised, while inclusion in innovative trials including re-irradiation, and phase I-II should be encouraged. A better understanding of underlying mechanisms of ependymoma cell will provide in the close future, the key to use targeted therapies at time of relapse, and very soon as first line therapy for some subgroups of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Ependymoma; Humans; Infant; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Procarbazine; Prognosis; Rare Diseases; Vincristine

Glioblastoma multiforme (GBM) invades beyond enhancing boundaries, and tumor cells are believed to exist in edematous peritumoral regions. We hypothesize that the concomitant treatment of both enhancing and FLAIR abnormalities on MRI by fractionated radiosurgery (FRS) would reduce local and regional recurrence. The purpose of this study was to demonstrate patterns of failure after FRS with simultaneous differential doses to two different target volumes of contrast enhancing lesions with/without FLAIR abnormality in recurrent GBM. Fifty-three patients with recurrent GBM were treated with FRS between 2008 and 2012. FRS was offered for the patients who had progressive tumors after the initial surgical resection followed by chemoradiation, and second-line chemotherapy. Radiosurgery Regimen A was 32 Gy (8 Gy × 4 treatments) to the contrast enhancing lesion only. Regimen B was 32 Gy (8 Gy × 4) to the contrast enhancing lesion and 24 Gy (6 Gy × 4) to the FLAIR abnormality delivered concomitantly. The study endpoint was radiographic failure on MRI at 2 months after FRS. Median survival after FRS was 7.5 months, and median progression-free survival after FRS was 4 months. Overall 82.4 % (42/51 lesions) recurred during follow-up. The local and regional failure rate was significantly lower in Regimen B (52 %) than in Regimen A (86.7 %) (p = 0.003). No sign of tumor progression in 10 % of Regimen A versus 28.6 % of Regimen B was shown during followup (p = 0.04). Instead, distant failure rate was higher in Regimen B. In conclusions, FRS was found to be a safe and effective salvage therapy for recurrent GBM. FRS to both contrast enhancing and FLAIR abnormalities appeared to improve local tumor control, and reduce regional tumor progression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Glioblastoma; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Postoperative Complications; Radiosurgery; Retrospective Studies; Treatment Outcome

This study investigates the outcome of children <10 years old with newly-diagnosed ependymoma treated on the prospective multinational "Head Start" III clinical trial. Between April 2004 and July 2009, 19 children with newly-diagnosed ependymoma were enrolled. All children were to receive five induction chemotherapy cycles followed by one consolidation cycle of myelo-ablative chemotherapy and autologous hematopoietic cell rescue. Children between 6 and 10 years of age or with residual tumor prior to consolidation were to receive irradiation thereafter. Median age of 19 children (8 female) was 20 months at diagnosis. Median follow up was 44 months. The primary site was infratentorial in 11 and supratentorial in 8 patients. Gross total resection was achieved in 10 patients. After induction chemotherapy, all three supratentorial ependymoma patients with residual disease achieved a complete response (CR), while only one of six infratentorial patients with residual disease achieved CR. Three infratentorial patients developed progressive disease during induction chemotherapy. All four infratentorial patients with residual disease who underwent autologous hematopoietic cell transplant, failed to achieve CR. Four patients received focal irradiation following chemotherapy. The 3-year event free survival (EFS) and overall survival (OS) for supratentorial ependymoma were 86 ± 13 % and 100 % respectively. The 3-year EFS and OS for infratentorial ependymoma were 27 ± 13 % and 73 ± 13 % respectively. The role of intensive induction and consolidation chemotherapy in deferring irradiation should be investigated further in children with supratentorial ependymoma with residual disease following surgery. This approach appears ineffective in children with infratentorial ependymoma in the absence of irradiation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Ependymoma; Etoposide; Female; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Prognosis; Prospective Studies; Radiotherapy Dosage; Survival Rate; Vincristine

We report on a 65-year-old female patient with a recent diagnosis of adenocarcinoma of the sigmoid colon and massive hematochezia in the context of a general bleeding disorder.. Disseminated malignant disease with hepatic metastases as well as bone marrow involvement was demonstrated. Moreover, circulating tumor cells were demonstrated by flow cytometry. The patient had right lower quadrant abdominal pain due to a spontaneous psoas intramuscular hematoma.. At the time of admission to our hospital, the patient displayed microangiopathic hemolytic anemia and secondary hyperfibrinolysis with a pronounced bleeding tendency. Moreover, there was an acute renal failure which improved with fluid resuscitation. With immediate chemotherapy consisting of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX regimen) and cetuximab initiated with the second course, plasmatic coagulation could be stabilized. Consequently, treatment with tranexamic acid, fibrinogen, fresh frozen plasma as well as red blood cell and platelet infusions could be stopped. Continuation of chemotherapy was possible on an outpatient basis and the further course was associated with a good quality of life until her near end. The patient died at home 7 months after initial diagnosis of her colon cancer due to progressive disease with CNS metastases.. Disseminated intravascular coagulation with microangiopathic hemolysis and secondary hyperfibrinolysis is a rare albeit possible event in disseminated colorectal cancer, especially when the bone marrow is involved. Treatment of the underlying cause is the most important therapeutic measure.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Neoplasms; Brain Neoplasms; Cetuximab; Disease Progression; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Fluorouracil; Gastrointestinal Hemorrhage; Hematoma; Hemorrhagic Disorders; Humans; Leucovorin; Liver Neoplasms; Neoplastic Cells, Circulating; Organoplatinum Compounds; Palliative Care; Purpura, Thrombotic Thrombocytopenic; Retroperitoneal Space; Sigmoid Neoplasms; Tomography, X-Ray Computed

Oxaliplatin is an anticancer agent only approved for treatment of colorectal cancer, but that has shown some activity in metastatic breast cancer in phase II studies. Herein, we examine the off-label use of oxaliplatin in unselected patients with metastatic breast cancer.. A retrospective review was performed of all patients with metastatic breast cancer treated with oxaliplatin at our hospital between February 2003 and November 2009. Data concerning patterns of use, safety and activity were collected from patient charts.. The cohort comprised 30 female patients with a median age of 49 (range, 34-68 years) and a median of two involved organs (range, 1-4). All patients had been pretreated for metastatic breast cancer (median number of previous lines: 3; range:1-6). Oxaliplatin was only given in association either with fluorouracil and folinic acid (n=23) or with gemcitabine (n=7). The most commonly used dose was 100 mg/m(2) given every other week or every 3 weeks. As of December 15, 2009, the median duration of treatment was 4 (range, 0.75-11) months. Most of the discontinuations occured due to disease progression (n=11) and adverse effects or worsening condition (n=8). Twelve (40%) patients presented side-effects related to oxaliplatin use including hematotoxicity (n=8), gastrointestinal disorders (n=4) and neuropathies (n=2). Among patients evaluable for antitumoral activity (n=15), one patient achieved a complete response and one patient demonstrated a partial response. Most of the patients (57%) continued to be treated by chemotherapy after oxaliplatin. Median overall survival for the evaluable patients was 10 (range, 1-51) months.. In our population of heavily pretreated women with metastatic breast cancer, off-label use of oxaliplatin was of little worth. This off-label treatment was not the last therapeutic option for most of these patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Off-Label Use; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Skin Neoplasms; Survival Rate; Treatment Outcome

High dose methotrexate has become one of the treatments of choice for patients with primary CNS lymphomas due to its ability to penetrate the blood-brain barrier. A potentially serious complication of this therapy is methotrexate-related nephrotoxicity. We report the case of a patient with a common genetic polymorphism that may have predisposed this patient experience clinically significant toxicity from systemic folate depletion. After the first cycle of chemotherapy that included high dose methotrexate, the patient's serum creatinine rose and the patient's methotrexate level remained above the toxic range for six days. On cycle two, the patient was treated with a 25% dose reduction in methotrexate and more aggressive hydration and alkalization. With this alteration in the regimen, the patient was able to receive six more cycles and had a complete radiographic tumor response in the brain and a disappearance of tumor cells in the CSF without any further renal complications. This case report illustrates the feasibility of administering high dose methotrexate with modifications as a treatment of choice in individuals with methylenetetrahydrofolate reductase gene mutations.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Leucovorin; Lymphoma, B-Cell; Male; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Genetic; Rituximab

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Mass Screening; Medical Oncology; Neoplasms; Organoplatinum Compounds; Societies, Medical

Intoxication due to insufficient renal clearance developed in 2 patients, a 54-year-old man and a 61-year-old woman, who were under treatment with methotrexate (MTX) for a primary cerebral lymphoma and a recurrence of large-cell B-cell-non-Hodgkin lymphoma, respectively. Both were treated with folinic acid rescue, thymidine, and alkalisation of the urine. MTX is a cytotoxic drug that is often used in oncology and rheumatology. Significant and even lethal toxicity can develop when the elimination ofMTX is delayed or when supportive care, such as folinic acid rescue, is inadequate. Delayed elimination can be caused by reduced renal function, by the 'third space' phenomenon such as in case of ascites, pleural fluid accumulation and oedema, and by drug-drug interactions leading to reduced renal function or a disturbance in the plasma protein binding ofMTX. Once toxicity has developed, the therapy must be directed at protection of the normal tissues, restoration of renal function and hence the renal elimination ofMTX, restoration of the alkalisation of the urine, and general supportive therapy.

Topics: Antimetabolites, Antineoplastic; Brain Neoplasms; Female; Humans; Kidney; Leucovorin; Lymphoma; Lymphoma, B-Cell; Male; Methotrexate; Middle Aged; Renal Insufficiency; Thymidine; Vitamin B Complex

Choriocarcinoma are malignant neoplastic tumors from the trophoblastic tissue with a tendency to early metastases. Beside pulmonary metastases there are often cerebral metastases, leading to intracerebral hemorrhage often responsible for the first clinical symptoms. In young women, symptoms like vaginal or pulmonary bleeding or neurologic disturbances shortly after a hydatiform mole or a normal pregnancy, accompanied by high levels of HCG in serum and CSF, choriocarcinoma should be considered. Choriocarcinoma are very sensitive to chemotherapy, which consists--depending on the stage of the disease--of a mono- or polychemotherapy. Cure rates are high, even in extended stages with cerebral metastases--as in the case described. Brain metastases with or without oncotic aneurysms can be rapidly controlled by immediate whole brain irradiation. Surgical interventions may be necessary in the case of life threatening bleedings. Levels of HCG in serum and cerebrospinal fluid are good markers to control the effect of therapy. But--as shown in this patient--levels of HCG in CSF may decrease protracted without affecting prognosis. Oncotic aneurysms are rarely reported and mostly detected post mortem. The presented case leads to a more optimistic attitude and demonstrates efficacy of immediately started radio- and chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blindness; Brain Neoplasms; Cerebral Angiography; Choriocarcinoma; Chorionic Gonadotropin; Combined Modality Therapy; Dactinomycin; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Intracranial Aneurysm; Leucovorin; Methotrexate; Pregnancy; Prognosis; Radiotherapy Dosage; Time Factors; Tomography, X-Ray Computed; Uterine Neoplasms; Vincristine

Thirty-two women with untreated metastatic breast cancer were treated with 100 mg/M2 i.v. methotrexate (MTX), 600 mg/M2 5-fluorouracil (5FU) and leucovorin 15 mg orally every 6 hr, 24 hr after MTX (MFL) on days 1 and 8 every 28 days. Stratification was according to sites of metastases (mets), adjuvant (adj), chemotherapy (CTX), and/or hormonal therapy or no adj therapy (Tx). Treatment continued until documented radiographic or clinical disease was in progression. Toxicity was mild, consisting of only minimal elevations of transaminases and mild cytopenias. There was no pulmonary toxicity. There were no hospitalizations, treatment delays or cessations for toxicity. One patient with skeletal mets had a complete response and 7 had partial responses. The overall median progression free survival (PFS) was 13.8 months (mos). Eighteen patients with skeletal mets had PFS from 7-70 mos (median 15.9). Five patients with lung mets only had PFS from 6-20 mos (median 9.8 mos). Patients with liver alone or with other visceral mets showed progression within 2-5 mos. However, patients with bone and visceral mets without liver involvement had PFS from 8-50 mos (median 20.5). Of 21 adj Tx failures the median PFS was 8.8 mos (2-94). Six who received adj CTX had a median PFS of 7.6 mos (3-12) and 4 tamoxifen (tam) failures a median PFS of 11 mos (8-15). Eleven patients who received adj CTX+tam had a median PFS of 8.5 mos (2-94). Six patients received tam at adj failure and MFL at progression. These six had a median PFS of 19.8 mos (8-50). The patients (six, who received no prior adj Tx) had a median PFS of 24.3 (8-70). MFL is as effective in achieving clinical remissions in metastatic breast cancer, is inexpensive and is far less toxic than other CTX regimes. MFL should strongly be considered as first line Tx.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Mitoxantrone; Prospective Studies

A 54-year-old patient with primary cerebral lymphoma was treated with two 4-weekly cycles of high-dose intravenous cytarabine (12 g/m2) and methotrexate (3 g/m2). The administration of the first course proceeded without notable complications. Before the administration of methotrexate in the second cycle blood cell counts and chemistry showed no abnormalities except for slightly increased alkaline phosphatase and gamma-glutamyl-transpeptidase levels which was attributed to diphantoin comedication. The patient developed symptoms of acute renal failure 7 h after methotrexate infusion which resulted in a very high serum methotrexate level (39.84 micromol/l) at 20 h after infusion. Rescue therapy was intensified: the leucovorin dosage was increased (1,200 mg continuous i.v. infusion every 24 h) and combined with thymidine rescue therapy (8 g/m2 per day continuous i.v. infusion every 24 h). Urine alkalinization was increased and diphantoin therapy was stopped. Leucovorin eye drops and mouth washes were started 5 days after methotrexate administration to prevent conjunctivitis and mucositis as a result of high methotrexate levels (>2.4 micromol/l). In spite of the fact that serum methotrexate levels remained persistently higher than 0.1 micromol/l for 12 days, the patient experienced no further short-term systemic toxicity except for anaemia (grade 3 according to NCI Common Toxicity Criteria). After day 12 intensified rescue therapy and the frequency of alkalinization were decreased to standard procedures and stopped on day 19. It is concluded that i.v. administration with high-dose methotrexate can result in unpredictable acute toxicity. In our patient, acute methotrexate toxicity was treated successfully by intensification of classical leucovorin rescue therapy in combination with thymidine infusion. In addition, leucovorin mouth washes and eye drops may have prevented mucositis and conjunctivitis, respectively.

Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Brain Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Lymphoma; Methotrexate; Middle Aged; Thymidine

The reduced bioavailability of chemotherapeutic agents is one of the reasons that explains the limited efficacy of adjuvant chemotherapy in high grade glioma patients. We report how even the results of high dose sequential chemotherapy can be influenced by antiepileptic drugs.

Topics: Adult; Anticonvulsants; Biological Availability; Brain Neoplasms; Breast Neoplasms; Chemotherapy, Adjuvant; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Glioma; Humans; Leucovorin; Methotrexate

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

Topics: Adolescent; Adult; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Dactinomycin; Etoposide; Female; Follow-Up Studies; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Middle Aged; Patient Compliance; Pregnancy; Prognosis; Retrospective Studies; Risk Assessment; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Brain Neoplasms; Cyclophosphamide; Doxorubicin; Fatal Outcome; Female; Humans; Leucovorin; Lymphoma, Large-Cell, Immunoblastic; Methotrexate; Prednisone; Radiography; Transplantation Conditioning; Vincristine

Gestational trophoblastic disease (GTD) forms a heterogeneous pool of clinically and histopathologically defined entities with different malignant potential. The clinicopathologic characteristics of 158 cases, including 110 complete hydatidiform moles (CHM), 13 invasive moles, 32 choriocarcinomas, two placental site nodules and one placental site trophoblastic tumor are reported. Of all cases, 63.9% showed spontaneous regression after D&C. 36.1% resulted in a persistent or metastatic (11.4%) disease, including 12 CHM. Lung is found to be the most common site of metastasis (61%). The median time between antecedent pregnancy and GTD was 4.4 months. 44% had an antecedent CHM, 16% a term pregnancy. The median complete remission rate was 91.2% with 5.3% recurrent disease. Three women died. Eight patients received adjuvant surgical therapy for chemoresistant foci. In general, management of GTD is interdisciplinary with an emphasis placed on individualized treatment. In most cases, exact histopathologic diagnosis of the trophoblastic lesion remains the gold standard for guiding clinical therapy. Currently, there are no reliable genetic or molecular biologic markers predicting an aggressive behavior of CHM. Thus, all lesions should be followed by serial measurements of serum-HCG. All cases of persistent GTD should be treated in specialized centers.

Topics: Adolescent; Adult; Age Factors; Brain Neoplasms; Choriocarcinoma; Drug Therapy, Combination; Female; Humans; Hydatidiform Mole; Leucovorin; Lung Neoplasms; Methotrexate; Middle Aged; Pregnancy; Risk Factors; Tomography, X-Ray Computed; Treatment Outcome; Trophoblastic Neoplasms; Trophoblastic Tumor, Placental Site; Uterine Neoplasms

A case of NHL which has been in long-term remission following vigorous treatment for CNS relapse with intrathecal administration of Ara-C and focal irradiation to the brain is presented. The patient was a 61-year-old man, who was successfully treated with CHOP followed by MACOP-B for diffuse large cell NHL in 1988. Five months later he was admitted to our hospital because of loss of visual acquity and numbness in the right upper and lower extremities. The presence of lymphoma cells in CSF, abnormal shadow in the left frontal lobe on a cranial CT scan and MRI scan, and positive Ga scintigraphy yielded a diagnosis of CNS relapse of NHL. Twenty one whole brain and additional 1.0Gy to the left frontal lobe of irradiation were performed. Eight days later the left tumor disappeared. Neurological remission was obtained and has continued until now.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Cyclophosphamide; Doxorubicin; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Prednisone; Remission Induction; Vincristine

In most reported series, less than 20% of patients with primary cerebral non-Hodgkin's lymphoma (PCL) and no known cause of immunodepression are alive and disease-free 5 years after the initial diagnosis. Whether chemotherapy improves the outcome of these patients remains unclear. We report a pilot study of a protocol (C5R) with 5 courses of chemotherapy followed by cranial radiotherapy in 25 adult patients with PCL and no known cause of immunodepression. The median age was 51 years (range, 16 to 70 years) and the median performance status was 2 (range, 1 to 4) in this series. Fourteen patients (56%) achieved a complete response and 4 (16%) achieved a partial response 1 month after the completion of the treatment. Four patients died in the first month of treatment because of progression (n = 1) or toxicity (n = 3). In 3 patients, the treatment could not be performed because of patient refusal (n = 1) or severe infections (n = 2). Myelosuppression was the most frequent side effect; febrile neutropenia occurred in 96%, 89%, 69%, and 74% of the patients after the second, third, fourth, and fifth courses of chemotherapy, respectively. Grade 4 thrombocytopenia occurred in 20% of the patients. With a median follow-up of 24 months, the projected survival of the group at 2 and 5 years is 70% and 56%, respectively. The 4 early deaths occurred in the subgroup of 6 patients greater than 60 years of age with an international prognostic index (IPI) greater than 3. In the 19 remaining patients (76% of this series) less than 61 years of age or with an IPI less than 4, the projected overall survival at 2 and 5 years is 88% and 70%, respectively. The C5R protocol is a highly efficient regimen in nonimmunosuppressed patients with PCL less than 61 years of age or with an IPI less than 4.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Protocols; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Feasibility Studies; Female; Folic Acid; Humans; Hydrocortisone; Leucovorin; Life Tables; Lymphoma, Non-Hodgkin; Male; Methotrexate; Methylprednisolone; Middle Aged; Pilot Projects; Platelet Transfusion; Prognosis; Prospective Studies; Survival Analysis; Survival Rate; Treatment Outcome; Vincristine

A retrospective series of 13 immunocompetent patients with histological diagnosis of primary central nervous system lymphoma (PCNSL) is presented. The series was divided into Group A, 6 patients treated with radiotherapy alone, and Group B, 7 patients treated with chemotherapy and radiotherapy. Clinicopathological patterns were similar for the two groups. In Group A, 4 patients achieved complete remission after radiotherapy (45-59.4 Gy) but relapsed within 9 months and died within 21 months of diagnosis. 4 Group B patients received chemotherapy followed by radiotherapy, and three who received a methotrexate-containing regimen are alive and disease-free at 34, 42 and 45 months, while the fourth died after 11 months. The other 3 subjects in this group were treated with radiotherapy followed by chemotherapy, and died within 15 months of diagnosis. Although radiotherapy is the standard treatment, chemotherapy has potentially an important role in the management of PCNSL. The sequence of combined treatment could be crucial to improvement of outcome.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Epirubicin; Female; Humans; Immunocompetence; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Prednisolone; Prednisone; Retrospective Studies; Survival Rate; Vincristine

We describe a 61-year-old man with a multiple neurologic complication of Merkel cell carcinoma, a rare skin cancer. An enhancing brain mass, and cytologically proven leptomeningeal disease produced a succession of symptoms including seizures, bilateral radiculopathies, myoclonus, a cauda equina syndrome and altered mental status. Aggressive treatment prolonged his survival marginally.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Merkel Cell; Cytarabine; Fatal Outcome; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Nervous System Diseases; Skin Neoplasms

The authors evaluated a high-intensity inpatient regimen using augmented but subtransplantation doses of multiple agents in patients with metastatic breast cancer. Two high-dose courses were given in an attempt to improve the efficacy of high-dose regimens using a single course.. Forty women received treatment between October 1988 and October 1991. The median age was 38 years (range, 24-56 years). Twenty-five patients were receiving their first chemotherapy for metastatic disease; 15 patients had received one or more prior regimens. The patients received two courses of chemotherapy, which consisted of the following: cyclophosphamide 1500 mg/m2 intravenously (i.v.) on days 1 and 2; doxorubicin 45 mg/m2 i.v. on days 1 and 2; cisplatin 20 mg/m2 i.v. on days 1, 2, 3, 8, 9, and 10; 5-fluorouracil 1000 mg/m2 on days 8, 9, and 10 (continuous infusion); methotrexate 100 mg/m2 i.v. on days 15 and 22; leucovorin 15 mg/m2 i.v. or by mouth for four doses beginning 24 hours after methotrexate. Etoposide 400 mg/m2 i.v. on days 1, 2, and 3 was substituted for doxorubicin in 14 patients who had received prior doxorubicin.. Twenty-nine of 40 patients (73%) had objective response to therapy, with 10 (25%) complete responses. Four patients who obtained a complete response remain disease-free at 14, 21, 28, and 32 months, respectively; all of these patients received this regimen as first-line therapy for metastatic disease. Myelosuppression was severe, with median durations of leukocytes less than 1000/microliters and platelets less than 50,000/microliters of 15 days (range, 7-48 days) and 13 days (range, 3-49 days), respectively. Moderate or severe mucositis occurred in 56 of 68 courses. Four patients (10%) had treatment-related deaths.. This regimen produced high overall response and complete response rates compared with standard regimens. However, only 15% of patients who received this therapy as first-line treatment for metastatic breast cancer remain disease-free, and median response duration was shorter than that reported using high-dose therapy with bone marrow support. Toxicity with this regimen was greater than anticipated, although myelosuppression and stomatitis would be reduced by the use of cytokines. This regimen does not improve results achieved with standard therapy sufficiently to justify its toxicity and expense.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Fluorouracil; Follow-Up Studies; Hemorrhage; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Methotrexate; Middle Aged; Neutropenia; Remission Induction; Survival Rate; Thrombocytopenia

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Fatal Outcome; Female; Fluorouracil; Gene Transfer Techniques; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Receptors, Estrogen; Salvage Therapy; Tamoxifen

Thirty-nine patients with choriocarcinoma and one with post molar trophoblastic tumour are presented. It was often found that there had been a long interval between the preceding pregnancy and the time of diagnosis or presentation. As a result, there was a high incidence of non-gynaecological presenting symptoms and 95 pc of our patients belonged to the high risk or poor prognosis group. The highest rate of cerebral metastases from choriocarcinoma so far reported in the world literature is presented here. At the beginning of 1987, a modified EMA regimen as introduced and has produced a great improvement in survival. The mortality from choriocarcinoma in Harare from 1985 to 1986 was 81 pc. In 1987 to 1988, this has fallen to 31 pc. The follow-up for the patients on the modified EMA regimen varies from four to twenty-four months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cause of Death; Choriocarcinoma; Dactinomycin; Etoposide; Female; Hospitals, Urban; Humans; Leucovorin; Methotrexate; Pregnancy; Prospective Studies; Retrospective Studies; Survival Analysis; Uterine Neoplasms; Zimbabwe

Combination chemotherapy with or without radiotherapy has had only modest efficacy in the treatment of primary CNS lymphoma. Median survival of these patients, treated primarily with radiotherapy, is 13 months; 5-year survival is less than 5%. Thirty consecutive non-acquired immune deficiency syndrome patients with primary CNS lymphoma were treated with barrier-dependent chemotherapy using intraarterial mannitol to open the blood-brain barrier (BBB). Follow-up included extensive neuropsychologic testing of all patients. Thirteen patients received cranial radiation 1 to 9 months before referral (group 1). Seventeen patients received initial BBB disruption chemotherapy with subsequent radiation only for tumor progression or recurrence (group 2). The difference in median survivals from diagnosis--17.8 months for group 1 and 44.5 months for group 2--was statistically significant (P = .039). Group 1 survival is comparable with the 20-month median survival of a historical series of patients (n = 208) treated with radiotherapy with or without chemotherapy. Group 2 patient survival represents an advance in the survival of CNS lymphoma and was associated with preservation of cognitive function in six of seven nonirradiated complete responders observed for 1 to 7 years. Patient toxicity was manageable in this intensive therapeutic regimen. In this series, a plateau in survival curves suggests that a major portion of these patients may be cured without the neuropsychologic sequelae associated with cranial radiation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Cognition; Cyclophosphamide; Dexamethasone; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Neuropsychological Tests; Procarbazine; Prognosis; Proportional Hazards Models; Survival Rate

Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5-5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 mumol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.

Topics: Adult; Aged; Astrocytoma; Blood-Brain Barrier; Brain Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fluoroimmunoassay; Humans; Leucovorin; Methotrexate; Middle Aged

Between 1986 and 1988 10 patients with primary cerebral lymphoma (PCL) were treated with initial MACOP-B chemotherapy followed by radiotherapy. All demonstrated radiological response to chemotherapy but this did not predict final clinical outcome. The overall median survival was 14 months. Patients with poor MRC neurological performance status (NPS) 2-4 had a median survival of 5 months. Three of 7 patients with NPS 0-1 died and the median survival is 18 months with a median follow-up of 13 months (10-35 months). The results were compared to 25 patients with primary cerebral lymphoma treated between 1963 and 1986 with radiotherapy as the main treatment modality. The overall median survival was 16 months. Patients presenting with poor NPS (2 and 3) had worse survival (median survival 8 months) compared to patients with good NPS (median survival 22 months; p less than 0.025). Patients diagnosed and treated from 1982 to 1986 also had significantly worse prognosis when compared to earlier treated patients. The preliminary results of combined modality therapy are so far not significantly different when compared to historical series and we have to await long-term outcome before recommending combined modality therapy as the treatment of choice.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Prednisone; Vincristine

Two children with primary intracranial mixed germ cell tumors are described who were successfully treated by partial resection of the tumor followed by sequential combination chemotherapy without radiation therapy. The chemotherapy consisting of VP-16 and cisplatin alternating with vincristine, methotrexate, and bleomycin resulted in apparent complete response after 6 to 7 months of treatment. Disease-free remission has continued 30-34 months off therapy. A small residual mass in one patient continues to decrease in size on magnetic resonance imaging and is presumed to represent postsurgical change rather than malignant tumor. This report demonstrates that chemotherapy may be effective in primary germ cell tumors of the suprasellar and pineal regions and could be considered for primary treatment instead of radiotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Child; Cisplatin; Combined Modality Therapy; Etoposide; Humans; Leucovorin; Male; Methotrexate; Neoplasms, Germ Cell and Embryonal; Postoperative Period; Vincristine

Choriocarcinoma is a rare malignancy in Scandinavia. We present a case of a young primigravida who experienced an uneventful pregnancy and gave birth to a healthy baby. Six days after delivery she underwent neurosurgery for intracranial hemorrhage. Pathological examination of the evacuated hematoma revealed metastatic choriocarcinoma. Further work-up exposed additional metastases in the lungs and liver. The initial serum level of human chorionic gonadotropin (beta-HCG) was 350,000 IU/I. Chemotherapy was given both intravenously and intrathecally. At 10 weeks, beta-HCG had returned to normal. Treatment was continued for another 10 weeks. Two years after cessation of therapy the patient is still in complete remission. In the discussion we review a scoring system to be used in selecting the mode of treatment, and briefly mention diagnosis and prognosis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Choriocarcinoma; Chorionic Gonadotropin; Chorionic Gonadotropin, beta Subunit, Human; Cyclophosphamide; Dactinomycin; Female; Humans; Leucovorin; Methotrexate; Peptide Fragments; Pregnancy; Sweden; Uterine Neoplasms

Intra-arterial high dose methotrexate (MTX) infusion therapy for ACNU resistant recurrent gliomas was reported. MTX was administered 16 times to 6 patients. In all cases, 20% mannitol was infused to produce a reversible osmotic blood brain barrier disruption. Dosage of infused MTX was 1,000-2,000 mg per an artery. One case revealed a complete response on CT. Another case showed an intratumoral necrosis. Intra-arterial high dose MTX infusion yielded high arterial and cerebrospinal fluid concentration of MTX. No critical complications were experienced. Dosage of MTX, an interval between the therapies and proper timing to start leucovorin rescue will be discussed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Drug Evaluation; Female; Glioma; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Mannitol; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Remission Induction

Although high-dose intravenous (IV) methotrexate (MTX) with leucovorin rescue (HDMTX) is effective for certain recurrent primary brain tumors, concern for inducing leukoencephalopathy has restrained its use as adjuvant therapy following therapeutic brain irradiation (RT). We have conducted a phase I to II clinical trial using four biweekly courses of HDMTX (8 g/m2) in a neoadjuvant setting in ten patients with newly diagnosed high-risk pediatric primary brain tumors. Four patients experienced an objective response after two to four courses of HDMTX alone (medulloblastoma, one; pineoblastoma, one; malignant cerebral astrocytoma, two). All ten patients subsequently received a course of therapeutic RT, and in seven cases, adjuvant chemotherapy with other agents. One patient acquired an acute transient encephalopathy before RT that completely resolved, and another developed a seizure disorder following RT associated with white matter abnormalities on a magnetic resonance imaging (MRI) scan. Five patients have survived a minimum of 33+ months, and four remain in continuous remission. The acute and delayed neurotoxicity of neoadjuvant HDMTX is acceptable, and we favor further use of this neoadjuvant approach in the context of a phase III trial.

Topics: Adolescent; Adult; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infusions, Intravenous; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate

From 1971 to 1981, twenty patients with poor-prognosis metastatic gestational trophoblastic neoplasia (GTN) were treated with moderate-dose methotrexate (1 g) and folinic-acid rescue (MD-MTX-FAR) as initial therapy. Seven (35%) were cured with MD-MTX-FAR, and salvage chemotherapy was successful in an additional seven, for a total cure rate of 70%. The ultimate outcome is similar to that reported for MAC triple therapy during this era. Hematologic and mucosal toxicity were negligible and no serious complications were encountered. We now use combination chemotherapy in patients with poor-prognosis GTN as first-line treatment. However, these results suggest that there may be advantages to the incorporation of MD-MTX-FAR in combination regimens in place of low-dose methotrexate, because of reduced toxicity and potential benefits for the prophylaxis and treatment of cerebral metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chlorambucil; Chorionic Gonadotropin; Combined Modality Therapy; Dactinomycin; Female; Humans; Hysterectomy; Leucovorin; Liver Neoplasms; Methotrexate; Pregnancy; Prognosis; Time Factors; Trophoblastic Neoplasms; Uterine Neoplasms; Vinblastine

Eleven patients with astrocytoma were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR). Clinical response was observed in eight patients, including four of four with grade 3 disease, one of one with grade 2 to 3, two of four with grade four, and one of one with unspecified low-grade tumor. Two patients with grade 4 and one with grade 1 disease failed to respond. Six of the eight responses were documented radiographically. Three of these patients are alive and well without further treatment for periods of 15+, 4.5+, and 1.5+ years. The fourth living patient is surviving 2+ years and improving under continued treatment. The four surviving patients had recurrent grade 2 to 3 or grade 3 disease. HDMTX-CFR is effective in astrocytoma. Its greatest value may be in recurring grade 3 disease.

Topics: Adolescent; Adult; Angiography; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Child; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neurologic Examination; Seizures; Tomography, X-Ray Computed

Topics: Adult; Brain Neoplasms; Broad Ligament; Choriocarcinoma; Female; Humans; Leucovorin; Methotrexate; Pregnancy; Pregnancy, Ectopic; Rupture, Spontaneous; Uterine Neoplasms

Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Combined Modality Therapy; Cyclophosphamide; Female; Glioma; Humans; Leucovorin; Lymphoma; Male; Mannitol; Methotrexate; Procarbazine; Tomography, X-Ray Computed; Water-Electrolyte Balance

Two biochemically different rescue agents, citrovorum factor (CF) and thymidine-inosine-allopurinol (TIA), were compared in an attempt to identify the mechanism for the increased therapeutic index achieved with high-dose methotrexate (MTX) plus rescue. Both CF and TIA were capable of protecting mice from MTX dosages up to 2000 mg/kg. Treatment of L1210-bearing mice with 2000 mg/kg MTX plus CF or TIA produced a 70 and 100% increase in life span, respectively, compared with 29% increase in life span achieved with the maximally tolerated dose of MTX alone. Bioassay of surviving peritoneal L1210 cells showed that a 4.5-log tumor kill occurred 24 hr after 2000 mg/kg MTX, while 400 mg/kg MTX produced only a 2-log cell kill. This differential tumor kill in the 4-hr period after MTX and prior to the onset of rescue accounted for the observed increase in animal survival times. In addition, treatment with 2000 mg/kg MTX resulted in a one-log-greater tumor kill of cells metastasized to the brain than did treatment with 400 mg/kg MTX. Following 2000 mg/kg MTX, additional tumor kill, as measured by bioassay, occurred during the period of TIA rescue but not during CF rescue, which was consistent with the observed differences in survival times between CF- and TIA-rescued mice. DNA synthesis in tumor and host tissue, as measured by the rate of [3H]dCyd incorporation into DNA, was cyclic after TIA administration but not after CF administration. The cyclic nature of DNA recovery in TIA-treated mice paralleled plasma kinetics of thymidine. It is postulated that " thymineless " intervals created by the rapid disappearance of thymidine resulted in inhibition of DNA synthesis and additional tumor cell kill during TIA rescue. Normal tissue did not appear to be adversely affected by exposure to these " thymineless " intervals.

Topics: Animals; Brain Neoplasms; Deoxycytidine; DNA Replication; Dose-Response Relationship, Drug; Hypoxanthine; Hypoxanthines; Inosine; Leucovorin; Leukemia L1210; Methotrexate; Mice; Thymidine; Thymine

Three patients with primary central nervous system (CNS) lymphoma have had major tumor regression with multiagent chemotherapy given in association with reversible blood-brain barrier opening used to enhance drug delivery to the tumor. In addition, in one patient barrier modification was carried out in the posterior fossa by mannitol infusion into the vertebral artery without untoward effects, an approach not heretofore accomplished. Computed tomographic (CT) studies documented that discontinuation of steroids rapidly effected an increase in the delivery of contrast agent to the tumor. CT monitoring of the degree of barrier modification showed tumor nodules and tumor size not apparent on the control scans, thereby providing additional evidence of the existence of a blood-brain barrier in CNS tumors. These studies further show that drug (contrast) delivery to the tumor, as well as to the surrounding barrier, is enhanced after reversible blood-brain barrier modification. Finally, chemotherapy administered by this approach resulted in defined, objective tumor responses in these three patients.

Topics: Adult; Aged; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Cyclophosphamide; Dexamethasone; Female; Humans; Hypertonic Solutions; Leucovorin; Lymphatic Diseases; Male; Mannitol; Methotrexate; Middle Aged; Procarbazine; Tomography, X-Ray Computed

Primitive neuroectodermal tumors are found in the cerebrum of children and young adults. The are clinically highly malignant and have rapid course from diagnosis to death. Their microscopic pathology reveals 90% to 95% nondifferentiation, frequent mitoses, and small dark cells with no observable cytoplasm. This paper discusses the treatment of three children with this tumor with a combination of surgery irradiation, and combination chemotherapy. The results of this approach are compared with previous reports in the literature. The average survival in this series is 24 months versus approximately 8 months reported in the literature.

Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; Carmustine; Child; Dexamethasone; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasms, Germ Cell and Embryonal; Procarbazine; Radiotherapy, High-Energy; Vincristine

Topics: Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Injections, Spinal; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Neoplasm Recurrence, Local; Norway; Pilot Projects

Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m2) the mean concentrations achieved 1 to 41/2 hours after the start of infusion were 1.3 X 10(-7) mol/l in cerebrospinal fluid and 1.7 X 10(-5) mol/l in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1 X 10(-7) mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1 X 10(-7) mol/l.

Topics: Brain Neoplasms; Child; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate

Thirteen patients with primary and metastatic CNS tumors have been treated with methotrexate (MTX) using three different approaches: (a) high-dose MTX with leucovorin (LV) rescue; (b) high-dose MTX with carboxypeptidase (CPDG) rescue; and (c) intraventricular administration of low doses of MTX for extended periods (concentration X time [CXT]). Eleven patients had central nervous system (CNS) lymphoma (one primary, one patient had recurrent medulloblastoma, and another patient had metastatic breast carcinoma. All 13 patients received high-dose MTX-LV rescue, while 3 patients were subsequently given MTX-CPDG. One patient received MTX by all three modalities. In patients with CNS lymphomas, complete responses (45%) and partial responses (36%) produced CNS disease-free intervals ranging from 1 to 23+ months. Survival for the complete responders has thus far ranged from 2.5 to 35 months, while the partial responders survived from 3 to 5 months. Two patients failed to respond and survived 2.5 and 3 months. Responses were obtainable with high-dose MTX-CPDG in patients resistant to MTX-LV. One patient who became sensitized to CPDG subsequently responded to MTX by intraventricular CXT administration. Thus, MTX can be effectively administered to patients with CNS tumors by several different approaches.

Topics: Adolescent; Adult; Aged; Brain Neoplasms; Breast Neoplasms; Carboxypeptidases; Female; Humans; Injections, Intraventricular; Leucovorin; Lymphoma; Male; Medulloblastoma; Methotrexate; Middle Aged; Time Factors

In summer 1978, Burkitt lymphoma was diagnosed in a 23 year old Swiss male. A brief report on this patient appears justified for the following reasons: (1) Burkitt lymphoma is very rarely diagnosed in Switzerland. (2) The tumor cells of this patient could be established as a cell line. They have now been subpassaged in vitro for over 9 months. (3) In contrast to the majority of non-African Burkitt lymphomas, these tumor cells produce small amounts of Epstein-Barr virus.

Topics: Adult; Brain Neoplasms; Burkitt Lymphoma; Cell Line; Cerebrospinal Fluid; Herpesvirus 4, Human; Humans; Leucovorin; Male; Methotrexate; Switzerland

A five-year-old girl developed acute myelomonocytic leukemia after fifteen months of intensive chemotherapy and irradiation for glioblastoma multiforme. The leukemia became manifest while the patient was in a remarkable remission brought about by treatment with high-dose methotrexate with citrovorum rescue. This is the first reported association of these disorders in the same patient. It is possible that the leukemia was induced by the treatment, since both radiation and the chemotherapeutic drugs used have been shown to be leukemogenic in some circumstances. The patient developed leukemia in a setting of relatively normal peripheral blood counts, having had very little myelosuppression from her treatment.

Topics: Antineoplastic Agents; Brain Neoplasms; Carmustine; Child, Preschool; Dexamethasone; Drug Therapy, Combination; Female; Glioblastoma; Humans; Leucovorin; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Methotrexate; Neoplasms, Multiple Primary

A comparison between citrovorum factor (CF) and carboxypeptidase G1 (CPDG1) rescue with respect to cerebrospinal fluid (CSF)-methotrexate (MTX) disappearance was studied in a patient with recurrent medulloblastoma who had a ventriculoperitoneal shunt. CPDG1 rescue resulted in a prolonged CSF-MTX half-life of 16.5-23 hours in comparison with CF rescue where the CSF-MTX half-life was 6.5-7.2 hours. There was a positive clinical response measured by loss of bone pain, increased physical activity, and almost complete clearing of CSF blast cells. CPDG1 rescue after high-dose MTX may provide more intense and selective treatment for meningeal neoplasms.

Topics: Adolescent; Brain Neoplasms; Carboxypeptidases; Drug Interactions; Drug Therapy, Combination; Humans; Kinetics; Leucovorin; Male; Medulloblastoma; Methotrexate

On the basis of activity against experimental tumors and potency as inhibitors of human dihydrofolate reductase, two compounds were selected for pharmacokinetic evaluation: metoprine ((2,4-diamino-5-(3',4'-dichlorophenyl)-6-methyl pyrimidine, DDMP, B.W. 197U) and etoprine, the corresponding 6-ethyl analog (DDEP, B.W. 276U). These lipid-soluble compounds readily cross the blood-brain barrier and penetrate rapidly into brain and brain tumors induced in rats by ethylnitrosourea. Both compounds are extensively bound to human plasma protein and their slow elimination from plasma and tissues contrasts with the kinetics of methotrexate. Cerebrospinal fluid levels of "folate" were elevated following oral administration of citrovorum factor to rats but not following equivalent doses of folic acid. The balance between selective action of the drug and selective protection by the vitamin is discussed with regard to differential distribution into separate compartments.

Topics: Administration, Oral; Animals; Brain; Brain Neoplasms; Dogs; Folic Acid; Folic Acid Antagonists; Half-Life; Humans; Leucovorin; Lipid Metabolism; Male; Models, Biological; Pyrimethamine; Pyrimidines; Rats; Solubility; Species Specificity

Eleven patients with brain tumors recurrent after surgery and radiation therapy were treated with high-dose methotrexate (MTX) (300-500 mg/kg) with citrovorum factor rescue (CFR). MTX was given as an iv infusion over 4 hours followed 2 hours later by oral CFR (10 mg every 6 hours X 12). MTX levels were measured in the serum, lumbar cerebrospinal fluid (CSF), and ventricular CSF at 0, 4, 12, 24, 48, and 72 hours from the start of the MTX infusion. MTX concentrations of greater than 10(-6) M were measured in the CSF over a period of 24 hours after the iv infusion. Peak CSF concentrations reached were greater than 10(-5) M. After the response to high-dose MTX with CFR was evaluated, vincristine (1.5 mg/m2) and a nitrosourea (methyl-CCNU or BCNU) were added to this treatment regimen. Two of four patients with recurrent pontine glioma and five of seven patients with recurrent medulloblastoma had favorable objective responses to treatment. It is suggested that high-dose MTX with CFR be cautiously considered for the primary treatment of intracranial neoplasms in children with the hope of increasing the cure rate for children with malignant brain tumors.

Topics: Brain Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Glioma; Humans; Leucovorin; Male; Medulloblastoma; Methotrexate; Neoplasm Recurrence, Local; Pons

Topics: Adult; Brain Neoplasms; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Humans; Infusions, Parenteral; Injections, Intra-Arterial; Leucovorin; Methotrexate; Middle Aged

Topics: Adolescent; Adult; Brain Neoplasms; Drug Therapy, Combination; Female; Glioma; Humans; Infusions, Parenteral; Leucovorin; Male; Methotrexate; Middle Aged; Nervous System

Multiple-dose toxicity of the 5-arylpyrimidine DDMP showed marked seasonal variation and sex dependence in BD2F1 mice. Considerable therapeutic activity against the ascitic, solid, and intracranial forms of Sarcoma 180 was demonstrated. Antitumor effects were highly schedule and dose dependent at a limited number of doses between 16 and 40 mg/kg. Antitumor activity (increase in lifespan) was approximately twofold greater against the ascitic tumor compared to the intracranial tumor at each dose level. The use of citrovorum factor rescue appeared to improve the therapeutic index of DDMP against intracranial Sarcoma 180 on specific multiple-dose schedules. Citrovorum factor rescue did not result in a greater initial antitumor effect of DDMP against the solid Sarcoma 180, but the effect was maintained for a longer period of time by allowing an increase in the number of doses which could be administered without toxicity.

Topics: Animals; Brain Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Folic Acid Antagonists; Leucovorin; Male; Mice; Pharmaceutical Vehicles; Sarcoma, Experimental

Topics: Adult; Antimetabolites, Antineoplastic; Blood-Brain Barrier; Brain Neoplasms; Child; History, 20th Century; Humans; Leucovorin; Leukemia; Methotrexate; Spinal Cord Neoplasms

Topics: Administration, Oral; Brain Neoplasms; Calcium; Child; Drug Evaluation; Glioma; Humans; Infusions, Parenteral; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Pons; Remission, Spontaneous

Topics: Aged; Astrocytoma; Brain Neoplasms; Catheterization; Craniotomy; Female; Glioblastoma; Headache; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Unconsciousness

Topics: Adolescent; Brain; Brain Neoplasms; Child; Ependymoma; Femoral Neoplasms; Humans; Injections, Spinal; Leucovorin; Male; Methotrexate; Neoplasm Metastasis

Topics: Adenocarcinoma; Arteries; Brain Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Catheterization; Chloramphenicol; Facial Neoplasms; Fever; Fluorouracil; Head and Neck Neoplasms; Humans; Infections; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Neoplasm Metastasis; Palliative Care; Penicillins; Stomach Neoplasms; Thoracic Neoplasms

Topics: Adenoma, Chromophobe; Adolescent; Adult; Aged; Brain Neoplasms; Child; Child, Preschool; Cobalt Isotopes; Female; Floxuridine; Folic Acid; Glioma; Humans; Infusions, Parenteral; Leucovorin; Male; Methotrexate; Middle Aged; Radioisotope Teletherapy

Topics: Animals; Antineoplastic Agents; Brain; Brain Neoplasms; Carotid Arteries; Catheterization; Cattle; Cerebral Angiography; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy; Leucovorin; Methotrexate; Neoplasms

Topics: Aphasia; Brain Neoplasms; Carotid Arteries; Cerebral Angiography; Drug Therapy; Glioma; Humans; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Necrosis; Paralysis; Parietal Lobe; Surgical Procedures, Operative; Temporal Lobe

Topics: Brain Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Melanoma; Methotrexate; Neoplasms; Palliative Care; Pelvic Neoplasms