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A Phase I trial of intraperitoneally administered 5-FU and citrovorum factor was performed in eight patients with a variety of malignancies. Both drugs were given according to a single weekly dose schedule in a volume estimated to be 2000 cc, including residual ascites. Citrovorum factor 50 mg was given first, immediately followed by 5-FU 1000-3400 mg, according to a dose-escalating schedule. Myelosuppression proved to be the dose-limiting toxicity, though mucositis, diarrhea, nausea, and abdominal pain were also produced. Six patients failed to respond to therapy. One patient with malignant mesothelioma showed a significant decrease in the production of malignant ascites and a transient conversion of peritoneal fluid cytologies from positive to negative, while a second patient with pancreatic cancer showed conversion of peritoneal fluid cytologies from positive to negative and demonstrated an objective partial response of an hepatic metastasis. Dosage adjustment according to body surface area would seem indicated by the toxicity data, with a 5-FU dose of 1200 mg/m2 body surface area and citrovorum factor 50 mg/m2 being recommended for Phase II trials of this combination of drugs given according to this weekly schedule.
In a randomized study, 35 patients with advanced-stage epithelial ovarian cancers with progressive disease after prior single alkylating agent or combination-agent chemotherapy were treated with either intermediate high-dose methotrexate-citrovorum factor rescue alone or methotrexate-citrovorum factor rescue plus cyclophosphamide. Objective responses to both "second-line" chemotherapeutic regimens were observed. The objective response rate of 43% observed with the methotrexate-citrovorum factor plus cyclophosphamide treatment was superior to that achieved with methotrexate-citrovorum factor given alone. This combination of agents is the most effective second-line chemotherapeutic regimen for ovarian cancer that we have yet tested and we are therefore optimistic about its possibilities as first-line therapy. After early dosage modifications, serious toxic side effects were rare in this group of patients who had had extensive prior therapy.
Thirty-three patients with gestational trophoblastic disease treated with methotrexate alone and 68 similar patients treated with methotrexate and citrovorum factor rescue were analyzed. Both groups showed a comparable sustained biochemical remission rate. The group treated with methotrexate and citrovorum factor however showed a shorter interval to induction of remission (p less than 0.05). Contrary to previous reports, the methotrexate and citrovorum factor regimen failed to protect the patients against the development of hepatic toxicity, the incidence of hepatic toxicity being significantly higher in the group treated with methotrexate and citrovorum factor.
The inhibitory action of sodium sulfadiazine on the growth of psittacosis virus (6BC) in embryonated eggs is readily reversed by citrovorum factor but not by small amounts of vitamin B(12). In embryonated eggs, the pteroylglutamic acid analogues, 9-methylpteroylglutamic acid and 4-aminopteroylaspartic acid, produced some suppression of the growth of psittacosis virus (6BC). 4-Aminopteroylglutamic add, 4-amino-N(10)-methylpteroylglutamic acid, and 4-aminopteroylaspartic acid inhibited the growth of this virus in tissue cultures at concentrations which were not toxic for the host tissue. The inhibitory action of 4-amino-N(10)-methylpteroylglutamic acid and 4-aminopteroylaspartic acid was readily overcome by addition of citrovorum factor. Growth of meningopneumonitis virus in embryonated eggs or tissue culture is suppressed by 4-aminopteroylaspartic acid. The advantages of the tissue culture technic for studies on the growth of viruses are discussed.
The present studies were performed to delineate the effect of high-dose methotrexate with citrovorum factor rescue on the measurable compartments of human granulopoiesis, including peripheral blood cells and bone marrow stem cells committed to granulopoiesis-monocytopoiesis. Parameters of granulopoiesis were determined during the first course of high-dose methotrexate with citrovorum factor rescue in five patients, and during four consecutive courses in one patient. The remarkably mild toxicity of high-dose methotrexate with citrovorum factor rescue reported in clinical studies was substantiated on the level of the committed stem cell compartment. The data suggest a higher sensitivity of in vitro colony-forming units in agar culture as compared to the more mature granulopoietic cells and document the exquisite sensitivity and regenerating capacity of erythroid precursors after this type of chemotherapy.
The effects of methotrexate on the DNA metabolism of human lymphoblast cultures and bone marrow cells were estimated. The ratio of the 3H-deoxyuridine and 3H-thymidine incorporation rates ia a good parameter for the methotrexate effect. Citrovorum factor (5-formyltetrahydrofolic acid) reverses methotrexate toxicity only when its concentration exceeds that of methotrexate at least ten times. Guidelines for the practice of high-dose methotrexate therapy and the following citrovorum factor rescue, especially for patients with retarded methotrexate elimination are presented. A new simple formula enables the exact calculation of the citrovorum factor dose for individual patients according to their methotrexate serum levels. This formula, derived from the experimental data of the bone marrow and lymphoblast culture cells, gives a rational basis for the high-dose rescue with citrovorum factor in cases with expected or manifest toxicity, and means, moreover, a safety factor for the practice of high-dose methotrexate therapy.
The use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) has considerably improved the prognosis of some pediatric malignancies. Massive doses of methotrexate (mtx) may lead to severe or even lethal toxicity. Safe administration of this regimen requires a wide pattern of laboratory tests as well as clinical supervision. One hundred and eighteen courses of HDMTX (12 gm/m2 over 6 hours iv) with CFR administered to 12 patients were analysed for changes of routine laboratory tests 0, 6, 24, 48, and 72 hours following infusion. Hgb, WBC, and platelets on average showed no change during the 72 hours follow-up period. Serum SGOT and SGPT were elevated with a maximum 24 hours following infusion and slowly returned to normal. The increase of serum LDH values were less marked and reached a maximum at 48 hours; changes of serum y-GT values were not significant. Evaluation of the elimination of mtx from serum in each individual patient throughout 14 sequential mtx courses gave no evidence of a prolonged serum half life due to impaired renal mtx clearance. There was also no evidence of enzyme induction in the liver resulting in a shortened serum half-life. Changes of serum enzymes also were not increasing throughout treatment. Careful monitoring of serum mtx levels is mandatory when HDMTX with CFR treatment is administered. Elevation of blood urea nitrogen and creatinine levels within 24 hours following mtx treatment identify the patient at risk for slow mtx elimination and severe toxicity requiring salvage by adequate doses of citrovorum factor.
A phase I study of 5-fluorouracil 600 mg/m2/week and folinic acid 500 mg/m2/week on day 1 and cisplatin administered weekly on day 2 was carried out on 30 patients with metastatic colorectal carcinoma of which 20 patients were pretreated with 5-fluorouracil. The first group of patients received cisplatin at the dose of 5 mg/m2/week. Cisplatin was then escalated to 10, 15, 20, 25, 30, and 35 mg/m2/week for subsequent groups of patients. Gastrointestinal side-effects were the dose-limiting toxicity. A therapy related death was seen at the dose of 35 mg/m2/week of cisplatin. The maximally tolerated dose of cisplatin in combination with 5-fluorouracil and citrovorum factor is 20 mg/m2/week. The optimally tolerated dose of 5-fluorouracil is 400 mg/m2/week in modulation with citrovorum factor 500 mg/m2/week. The recommended doses for a phase II study are cisplatin 20 mg/m2/week, 5-fluorouracil 400 mg/m2/week, and citrovorum factor 500 mg/m2/week.
The isolation of citrovorum factor from a chemically prepared mixture of the L(+/-) diastereoisomers (leucovorin) is described. The natural diastereoisomer was at least twice as effective as leucovorin in reversing methotrexate toxicity in mice.
Treatment of certain malignancies with high-dose methotrexate/citrovorum factor rescue has recently been adopted as an effective regimen. A microbiologic assay capable of detecting citrovorum factor in the presence of massive amounts of methotrexate has been developed using a strain of Pediococcus cerevisiae resistant to methotrexate. The assay described in this paper is an inexpensive and rapid method of studying the distribution kinetics of citrovorum factor.
Seven adult patients with advanced lymphoma, resistant to vincristine, prednisone, alkylating agents and Adriamycin were treated with "high dose" methotrexate and citrovorum factor rescue. Therapy consisted of 4 to 6-hour infusions of methotrexate (5--100 mg/kg) every 1 to 2 weeks with citrovorum rescue initiates 2 to 12 hours after termination of the infusion. Objective responses were obtained in three patients but these were short lived. Mucosal and hematologic toxicity occurred when repeat courses of therapy were administered. The results suggest that high dose methotrexate may be effective therapy in lymphoma, particularlly if citrovorum factor rescue is used early and in adequate dosage.
One hundred and thirty-four patients with advanced malignant disease were treated with 496 infusions of high-dose methotrexate (HD-MTX) followed by citrovorum factor rescue. Most patients had failed to respond to previous combination chemotherapy. The overall response rate was 29% with 33 partial responses and six complete responses observed in patients with a variety of tumors. Plasma MTX levels were monitored in all patients during each course of therapy in order to identify those patients with delayed plasma MTX clearance. Patients with abnormally slow rates of plasma MTX decay received escalated doses of citrovorum factor rescue in order to prevent drug-induced toxicity. In general, during this study HD-MTX was well-tolerated. Because serious toxicity was neither frequent, severe, nor unpredictable, its use was not limited. HD-MTX should now be evaluated in well-designed controlled clinical trials to compare its antitumor activity to that of conventional- or standard-dose MTX regimens in diseases where HD therapy appears to have efficacy.