Phase I trial of high-dose methotrexate with modified citrovorum factor rescue.
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MTX-CF therapy was administered in 13 patients with advanced renal cell carcinoma. 2 patients were treated with MTX single agent therapy at a dosage of up to 750mg/m2 per cycle and a short CF rescue of 48 hours. They showed partial remissions along with severe toxicity including gastrointestinal symptoms and bone marrow depression. 11 patients were treated by combination of MTX/CF, vincristine, bleomycin and an alkylating agent (either peptichemio or cyclophosphamide). In this latter group, patients with a glomerular filtration rate of more than 70 ml/min received 150 to 400 mg/m2 per cycle MTX. Patients with decreased renal function (glomerular filtration rate less than 70 ml/min) received 35 to 100 mg/m2 per cycle MTX. Two out of 7 patients with decreased glomerular filtration rate achieved remissions of more than 50%, two achieved remissions of less than 50% and two patients achieved static disease. Only one patient in the group of 4 patients with normal renal function showed a remission of more than 50%. Median survival time of patients in partial remission or with static disease was 24 months, of patients showing progression was 5 months. This difference is highly significant (p < 0.001). These results seem to justify further investigations of MTX/CF therapy in hypernephromas, even in the presence of impaired renal function.
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A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.
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Plasma methotrexate levels were measured in six patients with nonmetastatic and three patients with "low-risk" metastatic gestational trophoblastic neoplasia who were treated by two different methotrexate regimens. Five patients were treated with 16 cycles consisting of methotrexate, 1 mg/kg (days 1, 3, 5, and 7) followed in 24 hours by citrovorum factor, 0.1 mg/kg (days 2, 4, 6, and 8). Cycles alternated between intravenous and intramuscular administration. Statistical differences in plasma levels were found at 1 and 48 hours between the two routes of administration but probably were not of clinical importance. The plasma levels at the time of citrovorum factor administration were below that necessitating citrovorum factor rescue. Four patients were treated with alternating cycles of intravenous or intramuscular methotrexate, 0.5 mg/kg for 5 consecutive days without citrovorum factor. A total of 15 cycles demonstrated no difference in plasma levels at 1, 12, and 24 hours between intravenous and intramuscular administration. Statistical differences in plasma methotrexate levels were noted between the two methotrexate regimens only with intramuscular administration but were not of clinical importance. The reduced toxicity of the methotrexate-citrovorum factor may be due to the scheduling of the methotrexate and not to the citrovorum factor.
High-dose methotrexate-citrovorum factor rescue regimens are used extensively for the treatment of human malignancies. Since the rescue agent citrovorum factor is rapidly converted to 5-methyltetrahydrofolate, it is desirable to follow the distribution kinetics of both of these coenzymes to assess the selective therapeutic effectiveness of the regimen. The assay methods using methotrexate-resistant strains of Lactobacillus casei ATCC 7469 (LC/A), Streptococcus faecium var. durans ATCC 8043 (SF/A), and Pediococcus cerevisiae ATCC 8081 (PC/A) have been developed to determine the concentrations of 5-methyltetrahydrofolate and other folates in the presence of methotrexate. Since LC/A determines the total folates, SF/A deterimines the total folates except 5-methyltetrahydrofolate, and PC/A by our procedure determines only the most stable form of reduced folates, citrovorum factor, the quantitation of both 5-methyltetrahydrofolate and citrovorum factor can very easily be achieved by differential assays. This report describes the determination of as low as 10 ng/ml of 5-methyltetrahydrofolate in the presence of as high as 500 microgram/ml of methotrexate. The assay method described here is currently used in studying the pharmacokinetics of 5-methyltetrahydrofolate in patients with meningeal neoplasms.
The purpose of this study was to examine return of reproductive potential, hysterosalpingographic findings, and time to conception in patients treated with methotrexate and citrovorum factor for unruptured ectopic pregnancy. Fifty-seven patients with unruptured ectopic pregnancies less than 3.0 cm in greatest dimension were treated with methotrexate and citrovorum factor. The mean time from resolution of the ectopic pregnancy to return of menses was 26.0 (0 to 157) days. Forty-four patients were available for follow-up (2 to 15 months). Nineteen of 23 patients who had hysterosalpingograms demonstrated patency in the ipsilateral tube. Fourteen patients desired pregnancy; 11 of 14 (78.6%) were successful, with 10 of 11 (90.9%) having an intrauterine pregnancy, whereas one of 14 (9.1%) were extrauterine gestations. The mean time from first attempt to achieving pregnancy was 2.3 (1 to 4) months. We conclude that methotrexate and citrovorum factor treatment of unruptured ectopic pregnancy is associated with subsequent tubal patency and does not impair return of menses. Most importantly, the pregnancy rates after this form of therapy appear to be better than those achieved by traditional surgical methods, and are comparable to results after laparoscopic salpingostomy.
1. The effects of dietary biotin compared with vitamin B(12) on the total content and on the distribution of the various folate derivatives in the liver of rats given a biotin-free diet have been studied. The effect of both vitamins on the conversion in vitro of folic acid into citrovorum factor in the same experimental conditions was also examined. 2. In biotin-treated rats as well as in vitamin B(12)-treated rats the total content of folic acid-active substances measured microbiologically by Pediococcus cerevisiae, Streptococcus faecalis and Lactobacillus casei is significantly higher than that in biotin-deficient rats. The liver distribution of various folate derivatives in the three groups of animals is also markedly modified. 3. The amount of citrovorum factor formed in systems with liver homogenate of rats receiving biotin or vitamin B(12) is higher than that with liver homogenates of deficient rats. 4. The results obtained demonstrate the influence of biotin in the metabolism of folic acid, and the similar actions at this level of both biotin and vitamin B(12). These results are discussed in relation to the participation of the two vitamins in the metabolism of C(1) units, as a biochemical interpretation of the relationships between vitamin B(12) and biotin.