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Results for “CITROVORUM FACTOR”

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PubMed1979

[Reactive immunologic changes during intraarterial methotrexate therapy in patients with carcinoma of the oropharynx (author's transl)].

The immunity deficiency as colateral effect of intra arterial therapy with methotrexate in oropharynx carcinoma was measured by lymphocyte stimulation tests. Ten patients taken in two groups were treated with different doses of methotrexate and citrovorum factor. In determined stages of the cellular cycle an extensive reactive trauma to the lymphocytes was detected. This is not the case in the usual measurement of the number of lymphocytes, leucocytes and thrombocytes. This method seems to be appropriate in order to establish the doses, period of time and frequency for application of the intra arterial perfusion with methotrexate.

Adult↗

PubMed1981

Sequential combination chemotherapy of advanced head and neck carcinoma: re-evaluation of a highly effective regimen.

Twenty-seven evaluable patients with advanced head and neck squamous carcinoma were treated with a polychemotherapeutic regimen described in 1975 by Price et al. Chemotherapy consisted of vincristine, adriamycin, bleomycin, methotrexate, 5-fluorouracil, hydroxyurea, 6-mercaptopurine and citrovorum factor administered sequentially. One complete remission, 4 partial remissions, 7 minor responses were obtained for a total of 12/77 (44%) objective responses. Toxicity was acceptable. The results obtained were not better than those observed with less complicated regimens administrable on an outpatient basis.

Adult↗

PubMed1981

Methotrexate as a single agent and in combination chemotherapy for the treatment of non-Hodgkin's lymphoma of unfavorable histology.

High-dose methotrexate (HDMTX) with citrovorum factor (CF) was used to treat non-Hodgkin's lymphomas either as a single agent in those patients who had previously failed to respond to conventional chemotherapy or in previously untreated patients in combination with bleomycin, Adriamycin, cytoxan, and vincristine. Twenty-five patients who had been previously treated and were refractory to cytotoxic chemotherapy were treated with HDMTX ranging between 1 and 7.5 g/m2 as an iv infusion over 20 to 40 minutes. CF rescue was begun at 24 hours and was maintained orally every 6 hours at 10 mg/m2 for a total of 72 hours. In instances where the 24-hour serum level of MTX was in excess of 1 X 10(-7) M, the dose of CF was increased to 100 mg/m2 every 3 hours until the serum MTX level fell into the appropriate range. Of the 25 patients, 13 (52%) responded. Response duration was brief, lasting a median of 2 months. Three patients had prolonged control lasting 13, 16, and 21 months respectively. Five of the six patients with central nervous system (CNS) involvement have demonstrated marked clearing of spinal fluid abnormalities and reversion of brain scans toward normal. Fifty-four previously untreated patients with diffuse histiocytic or undifferentiated lymphoma have been treated with combination chemotherapy including MTX given at the level of 3 g/m2 on day 14 of a cycle. Bleomycin, Adriamycin, cyclophosphamide, and vincristine are given on Day 1 of the cycle. Dexamethasone 6 mg/m2 is given orally on Days 1 through 5. The cycle is repeated on Day 21, and patients are treated with 10 such cycles for a total of 30 weeks. Of our 42 patients who are evaluable for response and who have completed chemotherapy, 33 (78%) achieved a complete remission (CR). A total of seven patients have relapsed. Only one patient in the CR group has relapsed in the CNS after the cessation of chemotherapy.

Adult↗

PubMed1983

[Enhancement of tumor-specific killer T cell activities by high-dose methotrexate].

High-dose methotrexate (100 mg/kg) and citrovorum factor rescue enhanced syngeneic sarcoma (S1509a) specific killer T cell (cytotoxic T lymphocyte) in tumor bearing mice, although high-dose MTX suppressed killer T cell against S1509a in immunized mice. It was suggested that tumor specific suppressor T lymphocyte played an important role in enhancement of killer T cell. Enhancement of killer T cell was induced at day seven after administration of MTX. From the clinical point of view, weekly high-dose (100 mg/kg) MTX therapy may be necessary to enhance tumor specific immunity of the patients with sarcoma. High-dose MTX therapy is a unique one not only in practical point of view, but also in immunological point of view.

Animals↗

PubMed1982

Evaluation of the lipid-soluble diaminopyrimidines, metoprine and etoprine, in the avian sarcoma virus rat glioma model.

Using the avian sarcoma virus (ASV) rat glioma model, we have evaluated the in vivo effectiveness of two lipid-soluble folate antagonists, metoprine (DDMP) and its 6-ethyl analog etoprine. When adult Fischer 344 rats, which were previously inoculated with ASV as newborns, received DDMP ip, high levels of this drug accumulated in both normal and gliomatous brain tissue, as well as in lung and liver. When animals bearing ASV-induced gliomas were treated with DDMP or etoprine with or without citrovorum factor (calcium leucovorin), there was no increase in survival, even though the drugs were administered at maximally tolerated doses.

Animals↗

PubMed1984

Treatment of patients with metastatic osteogenic sarcoma: a report from the Children's Cancer Study Group.

Fifty-three patients with metastatic osteogenic sarcoma were treated with vincristine, high-dose methotrexate with citrovorum factor rescue, and cisplatin. Metastases were surgically removed in most patients, either prior to chemotherapy or following initial response to therapy. Among 29 previously treated patients, responses to initial chemotherapy included two complete remissions, six partial remissions, and eight patients with stable disease. Twenty-three patients were disease-free, six for greater than 12 months. Toxicity was moderate, but usually reversible. There were two toxic deaths and one unexplained death 48 hours following a dose of cisplatin.

Adolescent↗

PubMed1984

Methotrexate. II. Use in pediatric chemotherapy.

The comprehensive use of methotrexate is possible because there is an easy way of reducing the toxic effects of this drug. Effective in the antidotic action are alkalinization of the urine, increasing hydration of the patient, and "rescue" of purine and pyrimidine metabolism in the tissues by use of reduced folates. Only intravenous administration, by means of infusion given over a long period (24 hours or more), results in reliable and reproducible concentrations in the plasma. Oral administration should be abandoned because of the variable resorption and the different concentrations reached in plasma by different individuals. Local administration, such as by intrathecal injection, is useful only when the interval between two succeeding injections is 14 days or more. On the basis of known pharmacokinetic constants, the dose of methotrexate and of citrovorum factor (leucovorin) which will result in the desired concentration in plasma, and possibly also in tissues, can easily be calculated. Use of the principle of concentration X time in dosage calculations will result in the avoidance of giving unnecessarily high doses of methotrexate.

Administration, Oral↗

PubMed1984

[Evaluation of severe side effects of high-dose methotrexate in osteosarcoma].

Severe toxicity associated with high-dose methotrexate (HD-MTX) combined with citrovorum factor rescue (CR-Rescue) was evaluated in the 365 courses in 54 patients with osteosarcoma. Anaphylactoid reaction developed in 8 patients (14.8%), 8 courses (2.2%). The mean age was 14 years old. The total dose given was 85770mg in mean and 1840 mg per body weight (kg). The occurrence was proportional to the dose and the number of the course. Plasma MTX concentration remained under 10(-7) mol/l during the episode. Delayed clearance of MTX from plasma was treated with massive CF-Rescue in 10 patients (19%) (the mean age of 13.6), in 12 courses (3.3%), which was observed on an average at the 7th course when the total dose reached to 59530 mg, or 1390 mg per body weight (kg). Neurotoxicity was observed in only one patient (1.9%), one course (0.3%). Severe toxicity associated with HD-MTX therapy tended to occur according to dose escalation and the number of administration. To overcome severe toxicity careful observation of clinical symptoms and signs as well as adequate treatment of side effects without delay are of importance.

Adolescent↗

PubMed1983

Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis.

Serum and cerebrospinal fluid (CSF) concentrations of citrovorum factor (CF) and 5-methyltetrahydrofolic acid (5-MTHFA) were measured after i.v. infusion of leucovorin (50 or 100 mg/sq m) in seven patients undergoing treatment for meningeal carcinomatosis by intra-Ommaya reservoir injection of methotrexate (MTX). Serum CF levels rapidly rose after leucovorin administration as did 5-MTHFA, its conversion product. A small amount of CF entered the CSF, but peak CSF 5-MTHFA increased about 10-fold. The concentration X time (C X t) of additional 5-MTHFA in the CSF was greater [114.4 +/- 36.1 (S.E.) microgram/ml X min] after 100-mg/sq m doses of leucovorin than after 50 mg/sq m [14.2 +/- 4.3 micrograms/ml X min] (p less than 0.05). The CSF MTX concentration exceeded CSF 5-MTHFA by 2 to 3 logs throughout the 48 hr of observation, while serum 5-MTHFA and CF exceeded serum MTX by 0.5 to 2 logs. This study demonstrates that leucovorin administered i.v. to patients receiving intra-Ommaya MTX does not increase CSF concentrations of "rescue" folate above those of CSF MTX and are unlikely to interfere with MTX action against meningeal tumor. On the other hand, i.v. leucovorin does permit serum "rescue" folate to operate, thus reducing the systemic toxicity that may follow intraventricular administration of MTX.

Aged↗

PubMed1983

High-dose MTX/5-FU and adriamycin for gastric cancer.

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose methotrexate (MTX) and 5-fluorouracil (5-FU) combined with Adriamycin (ADM). In a pilot study we had found high-dose MTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman et al had shown synergism for this combination. The therapy protocol consisted of high-dose MTX, 1.5 g/m2 of body surface, and high-dose 5-FU, 1.5 g/m2. MTX was administered 1 hr prior to 5-FU. Both drugs were given as a bolus. Twenty-four hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q.6h. X 12, orally. Forty-eight hours after MTX administration, serum concentration of the drug was measured by high performance liquid chromatography (HPLC). Fourteen 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 should have a creatinine clearance of greater than 60 ml/min. The study included 30 patients with metastasizing gastric cancer and performance status between 40% and 70%. The response rate was 63% (19 of 30 patients). Two of 30 patients had complete remissions, which are still maintained. The median survival for responders is not yet evaluable: 68% are living after 17+ mo. The median survival for nonresponders was only 5 mo. The difference in survival curves is significant at a level of p less than 0.05. Cytostatic treatment was well tolerated. Fifty percent of the patients could be treated on an outpatient basis. Total alopecia was observed in only 10% of the patients. Severe leukopenia, thrombocytopenia, and kidney disorders were not observed.

Adult↗

PubMed1982

[Effects of a massive dosage of methotrexate and leucovorin rescue therapy on acute leukemia and malignant lymphoma].

The cooperative study group, consisting of 11 institutes, conducted a study by the high-dose methotrexate (MTX) with citrovorum factor (CF) rescue therapy on acute leukemia and malignant lymphoma that were resistant to other anti-cancer chemotherapy. In acute leukemia the rates of complete remission (CR) and partial remission (PR) were 16.7% and 26.7%, respectively, and in malignant lymphoma the response rate (excellent plus good response) was 38.9%. This therapy would be safely carried out by alkalinization of urine and adequate hydration under sufficient clinical surveillance. From the results of the present study, high-dose MTX-CF therapy seems to be one of effective regimens for acute leukemia and malignant lymphoma that are resistant to the conventional doses of MTX or other anti--cancer agents. Also, with this therapy, treatment or prophylaxis of symptoms of central nervous system and of other pharmacological sanctuaries can be expected, which may be one of the useful points of H-MTX-CF therapy.

Acute Disease↗

PubMed1983

Effect of "aminopterin" on epithelial tissues.

The folic acid antagonist, 4-aminopteroyl glutamic acid ("aminopterin"), is a potent inhibitor of growth and of connective tissue proliferation. The present study indicates that the suppressive effects of "aminopterin" on epithelial structures are more striking than on connective tissue, as revealed by observation of interference with wound healing and epithelization, atrophy and ulceration of mucosa, alopecia, and prompt suppressive effects in such dermatologic disorders as psoriasis and chronic indurative dermatoses. "Aminopterin" was administered orally in daily doses of 1.5 to 2.0 mg. to thirteen patients with psoriasis (of whom six had associated arthritis) and to five patients with chronic indurative dermatoses. The latter included one patient with chronic atopic eczematoid dermatitis with associated asthma, one with chronic eczematoid seborrheic dermatitis, one with chronic discoid lupus erythematosus involving the face, and two with scleroderma. In all patients there were remissions in cutaneous lesions, which appeared most commonly between the 5th and 10th day of "aminopterin" therapy. Treatment was interrupted in most patients after an initial course of 14 to 28 mg. because of the regular occurrence of shallow ulceration of the buccal mucosa and frequent development of abdominal cramps. Remissions persisted for periods ranging from two weeks to several months, after which lesions returned which responded to further courses of "aminopterin." The therapeutic response was more complete in the seven patients with psoriatic arthritis than in in six subjects with uncomplicated psoriasis. In four patients with psoriatic arthritis in whom the responses to "aminopterin" and cortisone were compared, arthritic manifestations were considerably more relieved by cortisone, but improvement in psoriasis was consistently more complete and more sustained with "aminopterin." No evidence of a summative effect of cortisone and "aminopterin" on psoriasis was observed when the two were employed concomitantly, although amelioration of arthritic symptoms was more complete than when cortisone was given alone. Topical application of "aminopterin" in a 1% ointment was found to be ineffective. "Aminopterin" is a toxic drug, and its administration must be carefully supervised. The citrovorum factor has proved useful in overcoming "aminopterin" toxicity but interferes with its therapeutic effects. It is suggested that "aminopterin" may prove useful in other dermatologic disorders and in cutaneous manifestations of some systemic diseases which, in certain instances, have been temporarily benefited by cortisone.

Adult↗

PubMed1981

Osteogenic sarcoma: eight-percent, three-year, disease-free survival with combination chemotherapy (T-7).

Sixty-one patients were treated with combination chemotherapy (T-7) for biopsy-proved, fully malignant, osteogenic sarcoma (OS) of the extremity. Chemotherapy consisted of the combination of bleomycin, cyclophosphamide, and dactinomycin, followed in 2 weeks by vincristine and high-dose methotrexate (HDMTX) given in doses of 8 g/m2 for adolescents and 12 g/m2 for children 12 years old or younger with citrovorum factor rescue. The HDMTX was administered weekly for 4 weeks. One week following the 4 HDMTX treatments, adriamycin (ADR) was given at a dose of 90 mg/m2 for 2 days. Two weeks after the ADR, 2 additional doses of HDMTX were given before surgery. Thirty-eight of the 61 patients were referred before amputation and underwent preoperative chemotherapy for approximately 3 months. After surgery, chemotherapy was resumed. Of the 61 consecutive patients with primary OS entered in the T-7 protocol, 54 (88%) remained free of disease for more than 8 to over 35 months (median 18+ mo), with a projected 3-year disease-free survival in excess of 80%. Of the 38 receiving T-7 chemotherapy before surgery, 28 demonstrated a near complete or complete lack of viable tumor cells on examination of the resected primary tumors. All 28 are surviving free of disease. Nine of the 10 patients less than 12 years of age remain free of disease from over 12 to more than 35 months (median 24+ mo). A significant increase in disease-free survival in the younger patients could presumably be attributed to the use of 12 g HDMTX/m2 in that age group. The prognostic value of the effect of preoperative chemotherapy on the primary tumor is statistically highly significant. These data indicated that preoperative chemotherapy with the proper dose of HDMTX would be valuable in all patients with OS.

Antineoplastic Agents↗

PubMed1981

Lymphoblastic lymphoma in adults: results of a pilot protocol.

Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.

Adolescent↗

PubMed1981

Selected applications of methotrexate alone and in combination in osteosarcoma.

Review of the reported use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CF) for treatment of primary and metastatic osteosarcoma indicates the rarity of responses in clinical situations other than treatment of the primary tumor or isolated pulmonary metastases with doses of 7.5 g/m2 or greater delivered on a weekly basis for 4 to 6 weeks. Adjuvant chemotherapy using HDMTX-CF at triweekly intervals has led to 2-year disease-free survival rates that are inferior to those obtained with combinations of agents including HDMTX-CF Adriamycin (Adria), with or without vincristine, cyclophosphamide, phenylalanine mustard, bleomycin, and dactinomycin. We concluded that although HDMTX-CF has a role in the treatment of primary and metastatic osteosarcoma, its use in combination with other active agents offers greater potential advantage to affected patients.

Antineoplastic Agents↗

PubMed1982

High-dose methotrexate and adriamycin in osteogenic sarcoma: the children's hospital of Philadelphia study.

From 1975 through 1979, 25 patients with osteosarcoma received therapy with vincristine, high-dose methotrexate, citrovorum factor, and Adriamycin. Five patients had metastases prior to receiving chemotherapy, and 11 of the remaining 20 nonmetastatic patients received preoperative or preirradiation chemotherapy. Chemotherapy caused objective tumor regression in 1 of 5 patients with metastases and 1 of 11 with measurable primaries. All five patients with metastatic disease died 7-16 months from diagnosis. Of the 20 nonmetastatic patients, 4 did not have primary amputations: all died. Of 16 patients with primary amputations, 6 are alive relapse-free 24-86 months from diagnosis, and 10 are dead. The actuarial survival of 36% is not statistically different from that of historical control groups or from that of concurrent control groups treated with surgery alone. However, because most adjuvant chemotherapy studies have involved few patients, 36% survival is not statistically different from the 50-70+% survival reported in previous studies. Our data fail to demonstrate that the adjuvant chemotherapy has improved the survival rate of children with osteosarcoma. We support a randomized, controlled comparison of adjuvant chemotherapy and aggressive surgical resection.

Actuarial Analysis↗

PubMed1982

Differential effect of high-dose methotrexate on erythropoiesis and granulocytopoiesis in humans.

The kinetics of erythroid and granulocytopoietic cell production were investigated during Courses 1 and 4 of high-dose methotrexate therapy with citrovorum factor rescue in a patient suffering from metastatic osteogenic sarcoma. Using the technique of quantitative 14C autoradiography, relative production rates were determined before, as well as 2, 24, 48, and 72 hr after, methotrexate infusion. There was only a minor decrease of the relative granulopoietic cell production 2 hr after methotrexate infusion followed by an overshoot reaction after 48 hr with a maximum of 3 to 4 times the pretherapeutic value. The relative erythropoietic cell production dropped to less than one-third of the pretherapeutic level during both courses and remained low during the period of postinfusion observation. The results indicate a severe and long-lasting impairment of the erythropoietic cell series, which is likely to include the committed stem cell pool. The impairment of granulocytopoiesis was much smaller and was followed quite soon by a reaction of recovery. The rate of DNA synthesis of individual cells was subnormal in all cell types investigated prior to Course 4 and was hardly affected by the methotrexate. Intracellular accumulation of methotrexate polyglutamates and differences in this pattern of accumulation between the red and white cell series are discussed as one possible explanation in this context.

DNA↗

PubMed1977

[Clinical observations on the use of high-dose methotrexate treatment in osteogenic sarcoma (author's transl)].

Since January 1976 high-dose methotrexate (HDMTX) therapy has been used in the management of patients with osteogenic sarcoma at the Orthopaedic Department, University of Vienna. 7500 mg MTX/sqm body surface is administrated in a four-hour infusion with citrovorum factor rescue. This therapy is combined with dactinomycin, adriamycin, bleomycin, cyclophosphamide and vincristine in a multi-drug chemotherapeutic program as a prophylactic regimen after surgical treatment of the primary tumour, as well as in the management of metastases. So far, 12 patients have received a total of 46 infusions with HDMTX at montly intervals (6 patients already had widespread metastases). The use of several precautions such as adequate hydration 3 l/sqm body surface fluid), systematic alkalinization of the urine and regular control of the serum MTX level renders HDMTX therapy less hazardous. Five out of the 46 infusions were followed by mild toxic reactions consisting of mouth ulceration, fever and/or bone marrow depression. One out of the 6 patients with metastases and 5 out of the 6 patients receiving HDMTX as a prophylactic measure are without evidence of disease at present. In view of the short observation period, this report is limited to clinical observations only.

Adolescent↗