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PubMed1981

Prognostic factors in the response of primary osteogenic sarcoma to preoperative chemotherapy (high-dose methotrexate with citrovorum factor).

Forty-three patients, ranging in age from 7 to 30 years (median age, 17 yr), with primary osteogenic sarcoma (OS), confirmed by biopsies and with no evidence of metastatic disease at the time of diagnosis, received T-7 chemotherapy for an average of 4 months before surgery, including high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR) (median, 7 courses), and 1 course each of bleomycin, cyclophosphamide, and dactinomycin, and adriamycin. At the time of definitive surgery, the surgical specimen showed a good histologic response to chemotherapy (grade III or IV response) in 29 (67%) of 43 patients and a poor histologic response (grade I or II response) in 14 (33%) of 43 patients. Among those who responded well, no patient relapsed, as all received a complete course of preoperative and postoperative chemotherapy for more than 5 to over 28 months after the initiation of treatment (medium, 13 mo). Among those who responded poorly, 6 of 14 patients relapsed with pulmonary metastases (a thoracotomy was beneficial to 1), 4 of 6 patients are alive with disease, and 1 patient died of progressive disease. On retrospective analysis, we observed that good and poor responders did not differ in the distribution of sex, age, race, primary site of disease, or histologic subtype of OS. An elevated alkaline phosphatase level that returned to normal under preoperative chemotherapy indicated a good response. Neither the 24-, 48-, and 72-hour serum MTX levels nor the fluid intake and urinary output during 3 days that followed HDMTX with CFR correlated significantly with tumor response. Based on our studies with this form of therapy, we concluded that the response of OS to preoperative chemotherapy is of prognostic value.

Adolescent↗
PubMed1984

Improved therapeutic index with high-dose methotrexate: comparison of thymidine-purine rescue with citrovorum factor rescue in mice.

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.

Animals↗
PubMed1976

Experimental chemotherapy with 5-arylpyrimidine antifolates: preliminary studies on toxicity and responsiveness of sarcoma 180 to DDMP (NSC-19494) and DDMP with citrovorum factor (NSC-3590).

The 5-arylpyrimidine antifolate DDMP showed appreciable therapeutic activity against an ascitic form of Sarcoma 180 in BD2F1 mice. Antitumor effects were highly schedule and dose dependent at a limited number of doses within the range of 8--40 mg/kg. The best results (increased lifespan = 112%) were obtained with two doses of DDMP at 40 mg/kg given 4 days apart. The incorporation of citrovorum factor rescue in dose schedules with DDMP appeared to improve the therapeutic index. In multiple-dose schedules with citrovorum factor allowing an average of eight doses of DDMP at a maximum level of 16 mg/kg, increases in median lifespan were greater than 158% with a number of long-term survivors.

Animals↗
PubMed1981

Differences in the pharmacokinetics of the diastereoisomers of citrovorum factor in dogs.

The pharmacokinetics of d- and l-citrovorum factor (CF) are quite different with respect to the postdistributional plasma decay rates. The natural (l) isomer had a half-life (beta) of 47 +/- 4 (S.E.) min compared to 143 +/- 15 min for the unnatural (d) isomer. Renal clearance was the same for both isomers and was proportional to glomerular filtration rate. Urinary excretion appeared to be the only route of elimination of the d isomer, while l-CF was extensively metabolized. Consequently, the unnatural isomer accumulated in great excess over the natural isomer and its active metabolite, 5-methyltetrahydrofolate. The apparent volume of distribution was about 58% of body weight for both isomers, which indicates that they have equal access to tissue compartments. The data suggest that d-CF can compete with l-CF and 5-methyltetrahydrofolate for entry into cells. Under certain conditions, accumulation of d-CF may interfere with rescue from methotrexate toxicity.

Animals↗
PubMed1977

Experimental chemotherapy with 5-arylpyrimidine antifolates: Further studies on toxicity and the responsiveness of ascitic, solid, and intracranial sarcoma 180 to DDMP and DDMP with citrovorum factor.

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.

Animals↗
PubMed1979

High dose methotrexate followed by citrovorum factor reversal in patients with advanced cancer.

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Adolescent↗
PubMed1980

Methotrexate-citrovorum factor used alone and in combination chemotherapy for advanced hypernephromas.

Methotrexate-citrovorum factor (MTX-CF) therapy was administered to 20 patients with advanced renal cell carcinoma. Eight patients were treated with MTX-CF only. Two patients who received short-term rescue showed partial remissions along with severe toxicity including gastrointestinal symptoms and bone marrow depression. Twelve patients were treated with a 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 greater than 70 ml/minute received 150-400 mg/m2/cycle of MTX. Patients with decreased renal function (less than 70 ml/minute) received 35-100 mg/m2/cycle of MTX. Two of seven patients with a decreased glomerular filtration rate showed partial remissions and four patients had static disease. One patient in the group of five with normal renal function showed static disease. None showed objective improvement. The median survival time was 25 months for patients with partial remission and static disease and 4.75 months for patients with progression. This difference is highly significant (P less than 0.0005). These results seem to justify further investigations of MTX-CF therapy in hypernephromas, even in the presence of impaired renal function.

Adenocarcinoma↗
PubMed1978

Methotrexate and citrovorum factor after histoincompatible allogeneic bone marrow transplants in dogs.

Methotrexate (MTX) followed by citrovorum factor (CVF) rescue was evaluated for its effectiveness in reducing graft-versus-host disease (GVHD) in lethally irradiated dogs transplanted with bone marrow from unrelated histoincompatible donors. Animals were given no immunosuppressive therapy (group A) or a combined regimen of MTX and CVF (group AMC). These two groups were compared with a group of animals transplanted earlier given MTX alone (group AM). Ainmals in the AMC group lived significantly longer than the A group (p less than 0.05). Engraftment rate, hematopoietic recovery and incidence of GVHD were similar in all three groups. Incidence of early deaths was significant in the AM group (p less than 0.05). It is concluded that MTX combined with CVF increases survival and is an effective posttransplantation immunosuppressive regimen with minimal toxicity.

Animals↗
PubMed1992

Cisplatinum in combination with 5-fluorouracil and citrovorum factor in the treatment of advanced colorectal carcinoma.

A phase II trial of citrovorum factor, 500 mg/m2/week, plus 5-fluorouracil, 400 mg/m2/week on day 1, and cisplatin, 20 mg/m2/week on day 2, was carried out in a group of 40 patients with metastatic colorectal carcinoma. A partial response with a mean duration of 8.4+ months was achieved in 24% of patients, a minimal response with a mean duration of 5.4 months was obtained in 6% of patients, and a stabilization of 6.2 months was achieved in 41%. Ten patients (29%) progressed. A 38% partial response rate was seen in patients with advanced rectal carcinoma, whereas no response was obtained in patients with colon cancer. Interestingly, 5 partial responses were seen in 12 patients pretreated with 5-fluorouracil. The overall survival was 9.8+ months. The mean survival of patients who achieved a partial response was 12.0+ months, whereas patients who progressed survived a mean of 6.6+ months. Patients with colon cancer had a mean survival of 8.1+ months, and those with rectal cancer survived a mean of 11.1+ months. This difference was not statistically significant. The treatment was generally very well tolerated, with patients showing mostly grade 1-2 gastrointestinal and/or hematological toxicity.

Adult↗
PubMed1978

Comparative effects of citrovorum factor and carboxypeptidase G1 on cerebrospinal fluid-methotrexate pharmacokinetics.

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.

Adolescent↗
PubMed1985

Response of astrocytoma to high-dose methotrexate with citrovorum factor rescue.

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.

Adolescent↗
PubMed1977

High-dose methotrexate with citrovorum factor in osteogenic sarcoma--progress report II.

Vincristine (VCR), high-dose methotrexate (MTX), and citrovorum factor (CF) were administered to 12 patients with classic osteogenic sarcoma with local control. Seven patients (58%) are free of pulmonary metastases for 2+-31/2+ years. With a second adjuvant program incorporating adriamycin (VCR, MTX, CF, and adriamycin), 16 of 20 patients are free of pulmonary metastases for 6+-18+ months. Five patients who developed pulmonary metastases were rendered free of disease by surgical resection. The VCR, MTX, and CF program was also administered at weekly intervals to eight patients with pulmonary metastases or unresected primary lesions. Two complete and one partial response were obtained in four patients with pulmonary metastases and three complete and one partial response were obtained in patients with primary lesions. This program was also administered in combination with radiation therapy to four patients who relapsed on conventional VCR, MTX, CF, and adriamycin therapy following surgical resection of pulmonary metastases. They remain free of recurrent disease for 2+-14+ months. There was no alteration in the incidence of toxicity when compared to earlier investigations. The results indicate that the VCR, MTX, and CF program has had a major impact on the management of osteogenic sarcoma.

Doxorubicin↗
PubMed1987

Methotrexate with citrovorum factor in low-risk gestational trophoblastic tumor.

From January 1976 through December 1985, methotrexate (MTX) with citrovorum factor (CF) was administered as primary treatment to 57 patients with low-risk gestational trophoblastic tumor (GTT); 51 patients were non-metastatic and 6 were metastatic GTT. The median number of courses needed to achieve biochemical remission was two (range, 1-7). Complete remission was attained in 95% of non-metastatic GTT patients with postmolar persistent trophoblastic disease, but when choriocarcinoma was histologically confirmed, this fell to 60%. The cure rate of metastatic GTT patients was only 50%. The overall remission rate with the MTX-CF combination was 84.2%. Toxicity was mild, consisting of myelosuppression and mucositis. Fifteen patients were resistant to MTX-CF, or relapsed subsequently, but they all achieved remission with chemotherapy rescue treatment (VP 16 alone, EMA/CO, CHAMOCA). Two patients required a pulmonary lobectomy. They are all still alive in biochemical remission with a median survival of 54 months. Our experience suggests that drug resistance and relapse rate seem related to a beta-HCG value higher than 10(4), an enlarged uterus with myometrial deep involvement, and a histologically confirmed diagnosis of choriocarcinoma. In conclusion, the MTX-CF combination is effective in postmolar GTT, whereas a different therapeutic approach may be considered for a "special" low-risk group of patients, on the basis of prognostic factors.

Female↗
PubMed1986

Experimental studies on high-dose methotrexate with citrovorum factor chemotherapy for 89Sr-induced osteosarcoma murine model.

Experimental chemotherapy using high-dose methotrexate (MTX) with citrovorum factor (CF) was performed on ddN strain mice bearing 89Sr-induced osteosarcoma and the antitumor efficacy was analyzed through autoradiography ([3H]thymidine). The administration was done using sustained infusion via the tail vein using our own device to maintain certain elevated blood levels of the drugs. As the first experiment, MTX was administered to 4 different groups of mice with dose levels of 250, 500, 1,000, 2,000 mg/kg for 6 hours followed by CF 200 mg/kg for 24 hours. It was found that the blood levels of MTX were maintained at 10(-4) M by the dosage of 500 mg/kg, but no higher levels were achieved by increasing dosage. Tissue such as the small intestine and the bone marrow recovered from the toxicity of MTX in about 1 week after the dosage of 500 mg/kg. In tumors, on the other hand, the tissue showed a gradual recovery with time, but the uptake of [3H]thymidine by the tissue was not restored to the pretreatment level. When the antitumor efficacy of a single dosage of 1,000 mg/kg and 2 dosages of 500 mg/kg each with 1 week interval were compared, the latter was definitely more effective. It was, therefore, concluded that the administration of the drugs should be done repeatedly with optimum doses of MTX and CF rather than with ultrahigh doses of MTX and CF all at once.

Animals↗