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PubMed1989

[Management of the administration of leucovorin calcium in high-dose methotrexate therapy].

At the Orthopaedic University Hospital Vienna, neoadjuvant chemotherapy with high-dose methotrexate (MTX) has been applied since 1975 in patients with osteosarcoma. Since 1977 the hospital has been a participant in the Cooperative German-Austrian Study on Osteosarcoma (COSS, 77, 80, 82, 85, 86). Therapeutic results and incidence of side effects are reviewed at regular intervals. Over a 2-year period (1/86 to 12/87), a total of 1999 g MTX were given to 15 patients in 102 therapeutic cycles. In patients treated with MTX in our hospital, only minor intolerance phenomena occurred, owing to careful leucovorin monitoring. Intoxications of up to grade III (modified WHO-score) have been seen in only a few patients. The management of the administration of leucovorin (leucovorin calcium, calcium folinate, INN; citrovorum factor) which is directly dependent on the serum level of MTX, is exactly shown in the discussion.

Adult↗

PubMedDate not supplied

Long-term results with FAMTX (5-fluorouracil, adriamycin, methotrexate) in advanced gastric cancer.

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose (HD) MTX and 5-FU combined with Adriamycin (ADM). In a pilot study we found HDMTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman and Bertino had shown synergism for this combination. The treatment protocol consisted of HDMTX, 1.5 g/m2 of body surface, and HD5-FU, 1.5 g/m2. MTX was administered 1 hour prior to 5-FU. Both drugs were given as a bolus. 24 hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q6h x 12, orally. 48 hours after MTX administration, the serum concentration of the drug was measured by HPLC. 14 days after MTX was given, ADM, 30 mg/m2, was injected as a bolus. This protocol was repeated every 28 days. Patients eligible for this treatment were required to have a creatinine clearance of greater than 60 ml/min. 116 patients with metastasized gastric cancer and a performance status between 40 and 70% were treated. The response rate was 58% (67/116 patients). 14/116 patients (12%) had complete remission. The median survival probability for all patients was 9 months, for responders 15 months, while for patients with complete response it has not been reached. The median survival for nonresponders was only 4 months. Around 10% of all patients lived longer than 6 years. The median follow-up-time was 4 years. Cytostatic treatment was relatively well tolerated. The deaths of 3 patients were drug-related. A quarter of all patients could be treated on an outpatient basis.

Adenocarcinoma↗

PubMed1979

Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma.

Plasma methotrexate (MTX) concentrations were determined in 52 patients after 409 infusions of high-dose (HD) (50-250 mg/kg) MTX with citrovorum factor (CF) rescue. In addition, detailed pharmacokinetic studies were conducted in nine of these patients. Plasma drug levels were compared at 6, 24, 48, and 72 hours from the start of MTX infusions in four different age groups (less than or equal to 10, 11-14, 15-17, and greater than or equal to 18 years of age). At the same drug dose, the younger patients had lower plasma MTX levels than the older patients at 6 and 24 hours. This difference increased in significance with increasing MTX dose. However, MTX plasma levels became similar at 48 and 72 hours, regardless of age. The half-life for the first phase of biphasic MTX clearance in children was shorter than that in adults. In addition, the urinary excretion of MTX was faster in younger children at all doses. The younger patients had a greater apparent volume of distribution of MTX after HD infusion. These results indicate that the age-dependent pharmacokinetics can be attributed to greater distribution and elimination of MTX in the younger patients. The potential difference in the metabolism of MTX between children and adults is currently under investigation. Our observations suggest that age exerts a dominant effect on the pharmacokinetics of HD-MTX.

Adolescent↗

PubMed1977

Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement.

Twenty patients with osteogenic sarcoma of the distal portion of the femur and the proximal portion of the tibia received chemotherapy (vincristine sulfate, methotrexate with leucovorin calcium rescue, [citrovorum factor; folinade calcium], and doxorubicin hydrochloride [Adriamycin]), followed by radical en bloc resection and prosthetic bone replacement. Histologic examination of surgical specimens obtained after chemotherapy showed variable degrees of tumor destruction and, in some cases, massive tumor necrosis, attesting to the profound effects of vigorous chemotherapy. This new therapeutic regimen, when feasible, may prove to be the treatment of choice in osteogenic sarcoma.

Adolescent↗

PubMed1977

Lipid-soluble diaminopyrimidine inhibitors of dihydrofolate reductase.

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.

Administration, Oral↗

PubMed1977

Aspects of the reversal of methotrexate toxicity in rodents.

An ip injection of a Lactobacillus casei dihydrofolate reductase preparation into rats and mice given a single lethal dose of methotrexate (MTX) caused a marked lowering of free MTX in the blood. Alternatives to citrovorum factor as agents for reversing MTX toxicity were explored in mice. dl, L-5-Methyltetrahydrofolate, dl,L-5,10-methylenetetrahydrofolate, l,L-5,10-methylenetetrahydrofolate, and dihydrofolate were also effective MTX antagonists; d,L-5,10-methylenetetrahydrofolate was inert.

Animals↗

PubMed1977

Analysis of methotrexate in human plasma by high-pressure liquid chromatography with fluorescence detection.

Methotrexate in human plasma at a concentration as low as 0.01 microgram/ml can be assayed with the use of high-pressure-liquid chromatography and a fluorescence detection system. Methotrexate is oxidized stoichiometrically to 2,4-diaminopteridine-6-carboxylic acid, a fluorescent product that is separable from other fluorescent materials in plasma with the use of an octadecylsilane (reversed phase) column. The detector response is linear over the range of 0.01 to 10 microgram/ml. Neither folic acid nor citrovorum factor interferes with the analysis. N-((4-([2,4-Dihydroxy-6-pteridyl)methyl]-amino)benzoyl))glutamic acid may be used as an internal standard, since it can be extracted from plasma and oxidized like methotrexate. The procedure is rapid (about 30 min) and should be a useful method for monitoring methotrexate plasma concentrations.

Chromatography, High Pressure Liquid↗

PubMed1979

Vincristine effect on methotrexate cerebrospinal fluid concentration.

A 67-year-old man with malignant lymphoma, nodular, poorly differentiated lymphocytic type, developed meningeal lymphomatosis. Repeated high-dose methotrexate-citrovorum factor treatment (1 g/m2 in 24 hours) rendered the patient free of disease. The administration of vincristine at 23 hours consistently increased the concentration of methotrexate in the cerebrospinal fluid 2.5-fold above baseline values.

Aged↗

PubMed1979

[Results and pharmacokinetic aspects of methotrexate therapy in high doses].

We used MTX as single drug treatment on the basis of an incremental dosage schedule, with doses increased from 250 mg/m2 to 750 mg/m2 or from 5 to 10 g, at intervals of 10 days. Moderately high MTX doses (750 mg/m2 at most) plus citrovorum factor rescue, failed to result in objective tumor regression in all of the 18 patients thus treated. High-dose MTX with CF rescue, by contrast, was found to produce partial remissions in 3 of the 19 cases treated thus far. Meticulous clinical monitoring and MTX serum level determinations are imperative for minimizing complications, if this drastic treatment regimen is employed.

Dose-Response Relationship, Drug↗

PubMed1987

[Autologous bone marrow transplantation in osteosarcoma].

Four patients with osteosarcoma were treated with intensive chemotherapy and autologous bone marrow transplantation (ABMT). The patients received high-dose methotrexate (9-12 mg/m2) with citrovorum factor rescue, high-dose melphalan (60 mg/m2 X 3), actinomycin D (0.5 mg/m2 X 3), adriamycin (30 mg/m2 X 2) and high-dose cyclophosphamide (60 mg/kg X 2) during 4 weeks. Bone marrow was aspirated and cryopreserved before treatment and reinfused 48 hours after the completion of chemotherapy. Two of four patients had advanced osteosarcoma with multiple pulmonary metastasis, one of whom had responded well and achieved partial response while the other had shown no response, and both patients died of disease progression 4 and 11 months after ABMT, respectively. The other two patients who received this regimen at an earlier disease stage for prevention of pulmonary metastasis, are alive and well without any evidence of metastasis 31 and 18 months after ABMT, respectively. This regimen was tolerated well in all patients except for mild nausea and vomiting. No infectious episodes were observed during the period of aplasia which continued for 19 to 38 days after marrow infusion. These results suggest that this supralethal combination chemotherapy is safe and tolerable when used with ABMT and effective for patients with osteosarcoma, especially when applied in the non-metastatic phase.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1977

Combination therapy for diffuse histiocytic lymphoma that includes antimetabolites.

Thirty patients with diffuse histiocytic lymphoma (DHL) were treated with one of three regimens that included cyclophosphamide, vincristine, methotrexate with citrovorum factor rescue, and cytosine arabinoside. Twelve patients had a complete response with a predicted 50% survival of at least 76 months. The medium survival of the 11 partial responders and seven nonresponders was 18 and 6 months, respectively. The addition of methotrexate and cytosine arabinoside may have a beneficial effect in therapy for DHL. From analysis of these results, there is reason to believe that efficacy may be partially dependent on the scheduling and dose of these two drugs.

Adolescent↗

PubMed1988

Corpus luteum activity in tubal pregnancy.

Corpus luteum activity was monitored in 20 women undergoing nonsurgical management of ectopic pregnancy with methotrexate and citrovorum factor (N = 15) or observation (N = 5). The functional integrity of the corpus luteum was assessed by measuring progesterone and 17-hydroxyprogesterone. Trophoblastic viability was assessed by measuring the immunoreactive beta subunit of human chorionic gonadotropin. Ten of 15 methotrexate-treated patients demonstrated initial progesterone levels above 1.0 ng/mL, declining to levels below 1.0 ng/mL after treatment. Five of 15 methotrexate-treated patients and all five managed by observation alone demonstrated progesterone and 17-hydroxyprogesterone values below 1.0 ng/mL both initially and throughout the surveillance period, leading to resolution, indicating previous death of the corpus luteum. We conclude the following regarding ectopic pregnancy: 1) Corpus luteum function declines early in the biologic history of some gestations while persisting in others, and 2) corpus luteum function varies from active to inactive independent of serum levels of immunoreactive beta-human chorionic gonadotropin.

17-alpha-Hydroxyprogesterone↗

PubMed1986

Treatment for osteosarcoma--a study of thirty-two patients treated with systemic chemotherapy and radical surgery.

Thirty-two patients with osteosarcoma of the femur and the tibia were treated with systemic chemotherapy and radical surgery between 1976 and 1984. Adriamycin (ADR) alone, ADR plus high-dose methotrexate with citrovorum factor (HD-MTX-CF) (protocol A) and ADR plus HD-MTX-CF plus cis-platinum plus bleomycin, cyclophosphamide and actinomycin-D (BCD) (protocol B) were given as chemotherapeutic regimens. Twenty-nine out of 32 patients received chemotherapy both preoperatively and postoperatively, and eleven of 29 patients had a good response. Amputation was performed on 19 patients and en bloc resection on 13 patients. No local recurrence was detected in any of the 32 patients. The disease-free survival rate was 35%. Disease-free survival rate of patients treated with protocol A and protocol B was 25% and 91% respectively. Fourteen out of 17 patients who developed pulmonary metastasis underwent thoracotomy. Survival rate after thoracotomy was 50%. The overall survival rate of 32 patients with osteosarcoma was 56%.

Adolescent↗

PubMed1978

Combination chemotherapy for osteosarcoma.

Because of the great risk for development of pulmonary metastases following amputation for osteosarcoma, 24 consecutive patients with "clinically localized" osteosarcoma of an extremity were given adjuvant combination chemotherapy with adriamycin-cyclophosphamide-high-dose methotrexate-citrovorum factor. Thirteen of these patients remain free of tumor from 11 to 48 months following amputation. The median disease-free survival is estimated to be 18 months and the median survival 27 months. No relapses have been observed in any patients surviving free of disease beyond 23 months. Combination chemotherapy was also given to 16 patients whose disease was not localized; eight with pulmonary metastases at or following diagnosis, one with nodal metastases at diagnosis, two with osteosarcoma following radiation therapy for other malignant tumors, three with osteosarcoma of flat bones, one with parosteal osteosarcoma, and one with multifocal osteosarcoma. Three of this latter group of patients are surviving free of tumor at 8, 17, and 19 months from diagnosis. Two young patients died from complications of methotrexate and adriamycin toxicity.

Adolescent↗

PubMed1978

Adjuvant chemotherapy for osteogenic sarcoma.

Twenty-nine evaluable patients with nonmetastatic osteosarcoma were given sequential combination chemotherapy utilizing high-dose methotrexate with citrovorum factor rescue, vincristine, adriamycin, and cyclophosphamide. Fourteen (48%) of 29 patients are currently disease-free for 8--48 months from initiation of chemotherapy with a median disease-free survival of 21 months. The projected 4-year disease-free survival is 13%. At 4 years the projected overall survival is 57%. In this particular study, adjuvant chemotherapy does not appear to significantly prevent the development of overt metastases. In four patients, delayed onset of metastasis was observed at 18--43 months from initiation of treatment.

Adolescent↗

PubMed1987

Bioavailability of high-dose oral leucovorin.

Fifteen adult subjects comprised the study group; 2 were colon cancer patients. Total leucovorin (citrovorum factor; CF) doses of 200, 400, 800, and 1600 mg were equally subdivided and administered at 0, 1, 2, and 3 hours. Three of the subjects were fasting and the other 12 were not. Quantitation of serum L-CF by Pediococcus cerevisiae and total reduced folates (TRF) by radio-assay were performed in 10 samples from each subject drawn over a 12-hour period after initiation of CF dosing. The mean serum levels of L-CF remained greater than 0.1 microM at 3 hours and the TRF 3.5 microM at 5 hours, respectively, after termination of CF dosing in all subjects treated at the 800- and 1600-mg dose schedule. At all CF dosage schedules employed, peak serum concentrations were reached within 4 and 6 hours after initiation of oral CF. Peak TRF concentrations at the 200-, 400-, 800-, and 1600-mg doses were 3.42 +/- 0.65, 4.05 +/- 1.04, 4.81 +/- 0.14, and 5.11 +/- 1.81 microM, respectively. Peak L-CF levels at 200, 400, 800, and 1600 were 0.15 +/- 0.11, 0.21 +/- 0.14, 0.23 +/- 0.11, and 0.34 +/- 0.16 microM. Based upon these observations, the following conclusions were reached: 1) no significant differences were observed in serum concentrations of folates between the 800- and 1600-mg dose schedules; 2) at these doses serum concentrations of L-CF and TRF were achieved that warrant a phase I investigation of high-dose oral CF with standard dose FUra in patients with advanced colorectal carcinoma.

Administration, Oral↗

PubMed1986

Rescue from high-dose methotrexate with 5-methyltetrahydrofolate.

5-Formyl-tetrahydrofolate [citrovorum factor (CF)] is commonly used for preventing or reversing toxicity due to treatment with high-dose methotrexate (HDMTX). In vivo, CF is converted to 5-methyltetrahydrofolate (MTHF) and then to the 5,10-methylene tetrahydrofolate, which is the active coenzyme involved in thymidine synthesis. In this study, MTHF was used for protection from toxicity following larger doses of MTX than previously studied, doses which could not be tolerated without effective "rescue." Fifteen patients were given 18 courses of MTX in escalating doses (1-24 g) followed by MTHF. The toxic effects observed included: leukopenia, thrombocytopenia, mucositis, nausea, vomiting, and elevation of serum creatinine and serum transaminase. The side effects were reversible and all patients recovered fully. "Matched pairs" comparison of CF and MTHF rescue in five patients showed no difference in rescue efficacy between the two agents. Since ten of the treatments consisted of 12 and 24 g of MTX, doses potentially fatal without rescue, MTHF is an effective agent for prevention of MTX toxicity.

Adult↗

PubMed1977

Microbiologic assays of cancer chemotherapeutic agents.

Among various assay methods available for the study of drug distribution kinetics in cancer chemotherapy, a method that determines the drug in its active form is the most desirable. The microbiologic assay method, with its rapid, simple, and inexpensive procedures, fulfills such a requirement. Besides the two commonly used chemotherapeutic agents, methotrexate and cytosine arabinoside, microbiologic assays are available for other chemotherapeutic agents, such as 6-mercaptopurine, 5-fluorouracil, actinomycin D, adriamycin, and daunorubicin. Assays have been developed for citrovorum factor and 5-methyltetrahydrofolate in the presence of high levels of methotrexate. With the introduction of combination chemotherapy, microbiologic assay methods using resistant mutants, sensitive to a single drug but resistant (either due to mutation or due to culture conditions) to all other drugs involved in the combination, could well be the most efficient for the study of distribution kinetics. Several such assay methods employed in our laboratory are discussed.

Antineoplastic Agents↗