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PubMed1987

Pathologic fracture in osteosarcoma. Impact of chemotherapy on primary tumor and survival.

Twenty patients with osteosarcoma and pathologic fractures were treated with a chemotherapeutic regimen consisting of cis-diamminedichloroplatinum-II (CDP), Adriamycin (ADR) (doxorubicin) and high-dose methotrexate with citrovorum factor "rescue" (MTX-CF). Before the introduction of the regimen, the primary tumor in two patients was treated by immediate amputation and in 13 with preoperative intra-arterial CDP. Among these 13 patients, responses (healing) were observed in 11 (one required the addition of radiation therapy). In three patients, the responses were so dramatic that, at their request, surgery was deferred and treatment exclusively with chemotherapy was instituted. Based on this experience, treatment exclusively with chemotherapy was also administered to an additional five patients who were admitted without pathologic fractures. In the course of such treatment, pathologic fractures also developed; notwithstanding, chemotherapy was maintained and healing also occurred. One of the 20 patients had pulmonary metastases at diagnosis; these were resected after treatment and pathologic examination revealed no evidence of viable tumor. The remaining 19 patients were free of pulmonary metastases but these later developed in seven patients. These data were compared to a historical control series in which 16 of 21 patients with pathologic fractures developed pulmonary metastases. Three of the chemotherapy treated patients died of nonosteosarcoma related causes (leukemia, generalized varicella, and a metabolic complication). Overall, survival was improved in the chemotherapy treated patients as compared to the historical control series: 10 of 20 versus 6 of 21, respectively. Pathologic fractures in osteosarcoma may heal under treatment with chemotherapy, which also has a favorable impact on the eradication of pulmonary metastases and survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1987

Metastatic hemangiopericytoma with prolonged survival.

A case of a hemangiopericytoma tumor metastatic to the lung from a central nervous system primary tumor in the posterior fossa is reported. The tumor was not responsive to treatment with cyclophosphamide, Adriamycin (doxorubicin), vincristine, DTIC (CYVADIC), high-dose methotrexate with citrovorum factor rescue, aziridinobenzoquinone (AZQ), or dibromodulcitol. However, the patient has had a prolonged survival, lasting for more than 26 years from original diagnosis, despite extensive recurrent primary disease and massive pulmonary metastases. Clinical and pathologic characteristics of these tumors are reviewed, with emphasis on the potential for long-term survival.

Adult↗

PubMed1978

Transient cerebral dysfunction following chemotherapy for osteogenic sarcoma.

An unusual neurological syndrome occurred in 4 of 158 patients treated for osteogenic sarcoma with combination chemotherapy. There was an abrupt onset of focal cerebral deficits approximately ten days after chemotherapy with vincristine and high-dose methotrexate plus citrovorum factor rescue. The syndrome was short lived and always occurred early in the course of treatment. Prolonged neurological deficits remained in 2 patients. When similar chemotherapy was reinstituted in the 4 patients, no further neurological complications ensued. Possible causes include a leukoencephalopathy related to methotrexate or an embolic cerebral vasculopathy related to necrotic tumor microemboli emanating from the lungs.

Adolescent↗

PubMed1978

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.

Adolescent↗

PubMed1979

Evaluation of overall toxicity of high-dosage methotrexate regimens.

The occurrence of overall toxicity was analyzed for 43 patients with osteosarcoma who received 349 high-dosage courses of methotrexate (HD-MTX) with citrovorum factor (Leukovorin) "rescue" (CF). The dosages of HD-MTX ranged from 50 to 350 mg/kg. Overall toxicity was assessed on the basis of five manifestations of toxicity: stomatitis, dermatitis, myelosuppression, liver dysfunction, and kidney function abnormalities. The great majority (91.4%) of the infusions were well tolerated, but 8.6% were associated with moderate or severe toxicity. Stomatitis and serum glutamic-oxaloacetic transaminase (SGOT) changes were the most frequent postinfusion findings. Three patients died from causes related to MTX toxicity. Dose, age, sex, and number of prior infusions were investigated by logistic regression analysis for prognostic effect on frequency of moderate to severe overall toxicity. Age and number of prior infusions had significant (P less than 0.06) effects on overall toxicity. Patients older than 15 years with greater than 10 prior infusions constituted the "high risk" group with a risk of moderate to severe toxicity 6.3 times that of the younger patients with fewer than 10 infusions.

Adolescent↗

PubMed1982

Plasma phenylalanine: tyrosine ratios during high-dose methotrexate-citrovorum "rescue".

We have measured phenylalanine and tyrosine in the plasma of patients with osteogenic sarcoma undergoing chemotherapy with high-dose methotrexate (HDMTX) citrovorum factor rescue (CFR). During 14 treatments in six different patients, the phenylalanine to tyrosine ratio (PHE/TYR) at 21 to 38 hours was elevated over pretreatment levels. The observed increase in plasma phenylalanine is attributed to inhibition by MTX of the phenylalanine hydroxylase system of the liver, which is not folate-dependent and thus is not corrected by administration of CV. A post-infusion increase in PHE/TYR of 571% after 22 hours in one patient and of 410% after 30 hours in another were associated with marked MTX toxicity. The greatest increase in PHE/TYR seen in a patient who did not experience toxicity was was 249% in 21 hours. Thus, in this group of patients, there appears to be a correlation between evidence of clinical MTX toxicity and the magnitude of the percentage increase in PHE/TYR in the plasma, which indicates inhibition of a liver enzyme and thus reflects the intracellular concentration of MTX.

Adolescent↗

PubMed1989

Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue.

Three adolescents and one child with osteosarcoma were studied during multiple courses of high-dose methotrexate, citrovorum factor rescue (HDMTX-CFR), with one adolescent treated intermittently over a period of 6 years. Plasma phenylalanine (Phe) and tyrosine (Tyr) were measured immediately before the infusion of MTX and then daily until serum MTX fell below 10(-7) M. At 24 hours, all showed marked increases in Phe and in the Phe/Tyr ratio. This suggests inhibition of dihydropteridine reductase (DHPR) which, in association with hepatic Phe hydroxylase, controls plasma concentrations of Phe. Inhibition of this enzyme system is not relieved by CFR. In the adolescent patients, although MTX levels in plasma declined steadily, Phe concentrations, which fell between 24 and 48 hours, rose to a new peak at 4-7 days. Possible reasons for this secondary increase are discussed. The patient with the longest exposure to HDMTX showed an increase in pretreatment Phe/Tyr ratios with time, suggesting damage to liver parenchymal cells not indicated by standard tests of liver function. Evaluation of plasma Phe during the course of HDMTX-CFR may permit assessment of intracellular concentrations of MTX or its metabolites in the liver without interference by CFR.

Adolescent↗

PubMed1994

Stage III abdominal non-Hodgkin's lymphoma in Costa Rican children: comparison of two consecutive trials of treatment.

Seventy-three patients with Stage III abdominal non-Hodgkin's lymphoma were prospectively treated following two sequential protocols (P): L278 P (group A, 33 patients) (1978-1983) and L384 P (group B, 40 patients), (1984-1991). No patient received radiotherapy. The L278 P included 7 drugs: cyclophosphamide, vincristine (VCR), adriamycin (ADR), prednisone, methotrexate (MTX), dexamethasone, and 6-mercaptopurine, given for remission induction, maintenance, and CNS prophylaxis. In the L384 P we introduced a consolidation phase consisting of intravenous MTX and citrovorum factor rescue, and IV cytosine arabinoside. VCR was also added to the monthly doses and the maintenance phase was reduced from 18 to 15 months. From January 1988 we changed ADR for epirubicin in the same doses. Prophylactic treatment of the CNS, in the L384 P, was intensified by increasing the number of doses of MTX IT in the remission, induction, and consolidation phases, and with the use of ara-C IT. Laparotomy in 50 patients allowed partial resection in 16, and second-look laparotomy was performed in 27 patients. Viable tumor was found in four patients. Three patients (G-A) died from metabolic complications and another 4 (2 G-A and 2 G-B) failed to attain CR and died. A total of 28 (85%) of 33 children of G-A and 38 (95%) of 40 children in G-B achieved CR. Five children died in remission (2 G-A, 3 G-B). Three patients (G-A) relapsed in the CNS and one (G-B) relapsed in the abdomen and died. Disease-free survival at 120 months was 70% in G-A and 84% in G-B.

Abdominal Neoplasms↗

PubMed1988

Overview: rational basis for development of fluoropyrimidine/5-formyltetrahydrofolate combination chemotherapy.

Fluorodeoxyuridylate (FdUMP) and thymidylate synthase (TS) are one of the better understood systems of drug-target interaction in cancer chemotherapy. Isolation and characterization of TS (initially from Lactobacillus casei and later from a variety of other sources), cloning and sequencing of the gene, determination of the 3-D structure of the enzyme by X-ray diffraction, and elucidation of the structure of both the catalytic intermediate and the enzyme-inhibitor complex have revealed critical parameters of the target at the molecular level. Potentiation of FdUMP binding by 5,10-methylenetetrahydrofolate (CH2-FH4), discovered at the enzymatic level, has been exploited to increase the clinical effectiveness of fluoropyrimidines. CH2-FH4 can be generated from folate, 5-methyltetrahydrofolate, or 5-formyltetrahydrofolate (citrovorum factor, CF); the latter is the compound of choice for therapeutic regimens. Transformation of CF to CH2-FH4 can occur via two pathways: (a) CF----5,10-methyltetrahydrofolate----CH2-FH4; or (b) CF----tetrahydrofolate----CH2-FH4. The relative importance of these pathways in various cells is not yet clear. The role of CH2-FH4 in FdUMP toxicity, and its central position in folate coenzyme-dependent C1 metabolism, emphasize the need for development of methods to quantitate intracellular levels of this compound.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1978

Adjvant treatment of tongue and floor of the mouth cancers.

Since January 1974, 95 patients with anterior tongue and floor of the mouth cancers were included in a randomized trial. After stratification according to staging and initial treatment, one-third of the patients received chemotherapy for 2 years (methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week, during the first 15 weeks), one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years, while the remaining third did not receive any treatment. If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate. Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors. Patients who previously received radiotherapy did not benefit from adjuvant therapy.

Antigens, Bacterial↗

PubMed1980

Biochemical control of high-dose methotrexate/Leucovorin rescue therapy.

High-dose methotrexate/Leucovorin rescue therapy is based on the assumption of differences in the transport system for folate compounds between normal and malignant proliferating cells. Thus, under normal conditions, methotrexate (MTX) and Leucovorin (citrovorum factor, CF) in low doses can enter the cells by an active transport system, whereas in some malignancies - such as osteosarcoma - these substances only penetrate through the cell membrane by passive diffusion if they are given in very high doses. Therefore, after high-dose MTX treatment, the cytotoxic effect of the folate antagonist is compensated for by rescue with Leucovorin in low doses only in the normal cell system. The consequence of this kind of treatment is a selective antitumor effect. To avoid cytotoxic side effects, this therapeutic regimen must be monitored carefully. The decrease of the ratio of 3H-deoxyuridine (dUR) beta H-thymidine (dTR) incorporation into the DNA of the cells is a good biochemical parameter for estimating the MTX effect on rapidly proliferating cell systems. Using this indicator, it was shown that the usually administered dose of Leucovorin is not sufficient for an effective rescue of the bone marrow cells as long as the MTX serum concentration is equal or higher than 10(-6) M. If in critical cases the MTX elimination is retarded, a rescue can only be achieved by Leucovorin at doses tenfold higher than the actual amount of MTX in the whole body system. The Leucovorin rescue does under such circumstances can be calculated according to the formula Leucovorin (mg) = 10 x MTX (mg/l) x 0.76 x body weight (kg).

Bone Marrow↗

PubMed1978

Pharmacokinetic and clinical studies of 24-h infusions of high-dose methotrexate.

Cytocidal activity of a drug is dependent on both drug dosage and duration of exposure. In contrast to the 'conventional" 6-h infusion and in an attempto to improve its efficacy, the high-dose methotrexate therapeutic regimen was given over a 24-h period with 10% of the dose administered in the first hour. Citrovorum factor was initiated at hour 24 and continued for 72 h. Treatment was administered every 2-3 weeks. 57 infusions were performed in twelve patients aged 7-20 years (six with osteogenic sarcoma and six with acute lymphoblastic leukemia). Determinations of serum methotrexate levels revealed that the levels were dependent on the dose. Levels assayed at 24 h revealed the following results: 4.4 +/- 1.4 x 10(-5) molar with 4.5 g/m(2), 2.04 +/- 0.34 x 10(-4) molar with 7.5 g/m(2) and 4.59 +/- 0.80 x 10(-4) molar with 12.5 g/m(2). Major toxicity was myelosuppression in 12 of 57 patients. There were no responses. The study demonstrates that 24-h infusions of high-dose methotrexate can be tolerated every 2-3 weeks in patients without bone marrow involvement and levels of at least 10(-4) molar can be maintained during the infusion.

Adolescent↗

PubMed1980

Clinical pharmacology of intermediate-dose oral methotrexate.

The clinical pharmacology of intermediate-dose oral methotrexate (MTX) was studied in nine patients receiving 18 courses of treatment. Serum and urine MTX concentrations were measured by means of a competitive protein binding assay after oral aqueous solution (3 courses), 50-mg tablets (13 courses) or IV drug (2 courses) had been administered in four doses of 100 mg/m2 at 6-h intervals or in four doses of 200 mg/m2 at 6-h intervals and followed by citrovorum factor rescue. Levels above 150 ng/ml (3.3 x 10(-7) M) were maintained throughout all treatment cycles, with rapid disappearance of drug after the last dose. A 100% increase in administered dose resulted in only a 42% increase in the concentration-time level. Methotrexate was absorbed well from both aqueous solutions and 50-mg tablets, but serum levels after 50-mg tablets were only 20% of those achieved after IV administration. We conclude that significant serum MTX concentrations can be achieved for prolonged periods of time after oral administration of intermediate doses, but that the proportion of drug absorbed is much less than is seen with lower doses.

Administration, Oral↗

PubMed1980

Microcinematographic study on the effect of methotrexate upon mouse mammary tumor cells (MMT cell line).

The effect of methotrexate (amethopterin) upon the MMT cell line was studied by time-lapse microcinematography, the plasma levels obtained after systemic administration of maximum tolerated doses of the drug in man being simulated in vitro. Cells in the logarithmic growth phase (large growth fraction population) were widely affected, although enough drug-resistant cells remained to regenerate the cell colony. Cells in the preconfluent growth phase (small growth fraction population) were less effected, because many cells were arrested at the GO-hase, outside the cell cycle. A drug-resistant colony always developed, making the drug therapy useless. The experiments showed that rescue treatment with leucovorin (citrovorum factor of folinic acid) was not effective either, because, at least on our experimental conditions, recovery of the mitotic activity was more rapid and the number of degenerating cells smaller with rescur treatment than with the conventional treatment. The results also suggested a new mechanism of methotrexate action in addition to the classic one of folic acid inhibition, which might consist in the inhibition of the production of formyl-methionyl-tRNA, part of the initiation complex in protein biosynthesis.

Animals↗

PubMed1979

Evaluation of 24-hour infusion of high-dose methotrexate--pharmacokinetics and toxicity.

High-dose methotrexate was administered by constant infusion over 24 h to children with various malignancies. Citrovorum factor was given at the completion of methotrexate infusion and continued for 72 h. Serum concentration of 10(-4) M could be sustained for 24 h with doses of methotrexate over 100 mg/kg. This infusion regimen was well tolerated and only mild neutropenia and mouth sores were seen in most patients. Severe toxicity was seen in one patient and was related to prolonged retention of methotrexate in the circulation. Careful monitoring of serum drug level is mandatory in the use of any high-dose methotrexate regimen.

Adolescent↗

PubMed1987

Prospective randomized cooperative medulloblastoma trial (MED 84) of the International Society of Paediatric Oncology (SIOP) and of the (German) Society of Paediatric Oncology (GPO).

This international, prospective, randomised therapeutic study is based on previous, separate studies of the two societies. The study asks two principal questions: Is it possible to improve the results of therapy by inserting, between surgery and post-operative irradiation, an intensive course of chemotherapy consisting of vincristine, procarbazine and methotrexate, followed by citrovorum factor rescue? In "low risk" patients (i.e. those with macroscopically "complete" resection and absence of metastases at diagnosis), can the radiotherapy to CNS areas outside the primary tumour site be reduced by 10 Gy with the aim of reducing late sequelae of irradiation but without compromising survival results? The study also aims at standardising diagnostic methods, neurosurgical procedure and radiotherapeutic technique employed in this tumour. For statistical reasons, results can only be disclosed after the end of the recruitment phase. It is intended to include approximately 350 patients in the study, which is planned to continue until the end of 1988.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1982

Treatment of patients with refractory myelogenous leukemia with BCOMM[1,3-bis-chloro(2-chloroethyl)-1-nitrosourea (BCNU), oncovin (vincristine), cyclophosphamide, high-dose methotrexate and methyl-glyoxal bis-guanylhydrazone (MGBG)].

Ten patients with AML refractory to anthracyclines and cytosine arabinoside were treated with vincristine 1.4 mg/m2 and methotrexate (MTX) 2.5 gm/m2 by intravenous (IV) bolus on day 1 [citrovorum factor (CF) rescue began 24 h later], BCNU 80 mg/m2, and cyclophosphamide 900 mg/m2 IV 36 h after MTX and MGBG 300 mg/m2 IV over 1-2 h on days 3, 4, and 5. Bone marrow aplasia was achieved in all patients by day 12. Five patients (50%) achieved complete remission (CR). Two patients died of sepsis during induction. The median duration of remission was 24 weeks (range 8-38). Maintenance therapy was employed in three patients (high-dose MTX-CF in 2 and MGBG plus BCNU in 1), but did not appear to significantly increase the duration of remission. Nausea and vomiting occurred in eight patients. Five patients developed moderate stomatitis and one developed a moderately severe cutaneous reaction. This pilot experience demonstrates that patients with refractory AML can achieve CR after aggressive treatment with so-called second-line drugs. and may indicate that collateral sensitivity to MTX exists in cells which have become resistant to anthracyclines, a situation we previously described in an experimental cell line.

Adolescent↗

PubMed1978

Leukoencephalopathy following high-dose intravenous methotrexate chemotherapy: quantitative assessment of white matter attenuation using computed tomography.

A clinical or subclinical leukoencephalopathy occurs in some children after treatment of acute lymphatic leukemia with prophylactic cranial radiation therapy and parenteral or intrathecal methotrexate. We have observed a similar clinical leukoencephalopathy in patients with bone tumors treated with intravenous high-dose methotrexate and citrovorum factor without cranial irradiation. CT scans of such patients may indicate decreased white matter attenuation, but visual appraisal of this phenomenon is occasionally misleading. A computerized method for analyzing white matter hypodensity by determining the mean attenuation coefficient for one or several contiguous CT slices has therefore been developed. Serial comparisons of this mean attenuation coefficient appear to be more reliable than simple visual appraisal.

Adolescent↗