Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9 patients with osteosarcoma were treated with a total of 122 infusions of high-dose methotrexate (MTX; 140-350 mg/kg) followed by leucovorin rescue. Plasma kinetics of MTX and 7-hydroxymethotrexate (7-OH-MTX) has been routinely monitored. Due to inadequate hydration and alkalinization, 1 of the 122 high-dose MTX infusions was followed by delayed disappearance of MTX and 7-OH-MTX from plasma with subsequent development of severe mucositis. Serious hepatotoxicity repeatedly developed in another patient with inconspicuous MTX kinetics. The benefit of monotherapy with high-dose MTX for adjuvant treatment of osteosarcoma remains questionable, since 6 of 8 patients with primary osteosarcoma developed pulmonary metastases within 4-12 months (median 5 months), 2 have been disease-free and alive for 25 and 53 months.
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PMID:High-dose methotrexate for osteosarcoma: toxicity and clinical results. 660 Aug 27

Osteosarcoma patients free of CNS metastases are at risk for acquiring leukoencephalopathy after receiving multiple courses of high dose intravenous methotrexate followed by oral leucovorin rescue (MTX-LV). A prospective study of the adequacy of CNS rescue of MTX biochemical toxicity by oral leucovorin was undertaken in newly diagnosed neurologically normal osteosarcoma patients. Prior to surgical resection of the primary tumor, ten patients received 4 weekly courses of MTX-LV. During the fourth weekly MTX-LV treatment, 0 and 72 hr serum and CSF determinations of MTX, 5-methyl-tetrahydrofolate (5-MTHF) and LV were made. No CSF MTX was detectable at 0 hr in any patient, but a significant elevation in CSF MTX occurred in 9/9 patients at 72 hr (mean 47.2 +/- 31.8 ng/ml or 1.04 +/- 0.7 X 10(-7) M). There was no significant change in mean CSF 5-MTHF over 72 hr despite a rise in serum 5-MTHF. MTX exceeded 5-MTHF in 6/9 patients in CSF, whereas only 3/8 patients had higher MTX in the serum at 72 hr. No acute systemic or neurotoxicity was seen. The failure of oral leucovorin to consistently elevate CSF 5-MTHF levels at 72 hr in the context of significant levels of CSF MTX may result in intermittent CNS folate deficiency. The clinical and pathological syndrome of leukoencephalopathy may be related to this phenomenon and may evolve after repeated MTX-LV treatments.
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PMID:The inability of oral leucovorin to elevate CSF 5-methyl-tetrahydrofolate following high dose intravenous methotrexate therapy. 661 87

We have studied gonadal function in five patients (three men and two women) who received high-dose methotrexate (HD-MTX) alone and in 12 patients (seven men and five women) who received HD-MTX and vincristine (VCR) as postoperative adjuvant therapy for osteosarcoma. Testicular function was assessed by determination of testicular size, sperm concentration, and serum follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone levels while evaluation of ovarian function was based on menstrual history and serum FSH, LH, estradiol, and progesterone levels. The two women who received HD-MTX and all five women who received HD-MTX and VCR had regular cyclic menses not only after therapy but also during treatment. Serum FSH, LH, estradiol, and progesterone levels were normal in all women studied. Among the ten men studied, testicular function was normal in the six patients evaluated initially several months after the completion of therapy. In contrast, severe oligospermia was noted among four men evaluated during and immediately after treatment. From serum samples obtained before, during, and after treatment we have determined that approximately one half of the men who received HD-MTX alone or in combination with VCR develop transient testicular failure associated with a significant increase in serum FSH but not LH levels. Sperm concentration and serum FSH levels then return to normal after completion of chemotherapy.
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PMID:Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. 679 18

Twenty year's (1959-1979) experience in the treatment of osteosarcoma at the Bone Tumor Center of the Istituto Ortopedico Rizzoli is presented. During this period 433 cases were recorded, but only 266 were considered. All the patients underwent surgery but after 1970 whole-lung irradiation (1971), immunotherapy (1971), and chemotherapy (1972 onward) were added as adjuvant therapies on a nonrandomized basis. In the group treated with surgery alone the prognosis was very poor: 10% survived nine years or more after the diagnosis, an average disease-free interval of 7.7 months and an average survival time of 13 months. Monolateral whole-lung irradiation had negative results and was abandoned after six cases. Adjuvant immunotherapy with irradiated autologous tumor cells gave moderately positive results in 16 patients, but only by delaying the appearance of first metastases, therefore increasing the time of survival. Adjuvant chemotherapy was performed with three different protocols: one protocol with ADM only and two protocols using VCR + MTX (at medium dose) + ADM, administered according to two different schedules. Superimposable results were obtained with these three regimens. With equal follow-up, the percentage of continuously disease-free patients treated with adjuvant chemotherapy was significantly higher than that of patients treated with surgery alone (P less than 0.001). The patients in the chemotherapy group who had relapses showed a prolonged time (mean = 12.3 months) to the onset of the first metastasis. Adjuvant chemotherapy caused virtually no morbidity and no deaths. Reference is made to the advantages of a large and homogeneous caseload deriving from a single institution to avoid preselection bias and evaluate the effectiveness of new therapeutic approaches when patient randomization has not been employed.
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PMID:The treatment of osteosarcoma of the extremities: twenty year's experience at the Istituto Ortopedico Rizzoli. 694 43

The pharmacokinetics of methotrexate (MXT) and 7-hydroxymethotrexate (7-OH-MTX) has been studied in seven patients treated for osteosarcoma with up to 27 cycles of MTX at doses of 140-350 mg/kg of body weight. The distribution volume of MTX was 0.186 +/- 0.062 liter/kg. Peak plasma levels ranged from 540 to 1700 microM for MTX and from 12 to 560 mu M for 7-OH-MTX. The MTX metabolite 2,4-diamino-N10-methylpteroic acid was occasionally detectable in plasma and urine at a level of 10(-7)M. Plasma disappearance of MTX was biphasic, with a terminal half-life of 2.1 +/- 0.6 hours (mean +/- SE). Plasma decay of 7-OH-MTX was mainly monoexponential, with a half-life of 23.8 +/- 15.2 hours. The renal clearance of MTX (0.0623 +/- 0.0232 liter/kg/hour) accounted for about 84% of the total clearance of MTX (0.0742 +/- 0.0288 liter/kg/hour). In urine, 70%-94% of the dose was recovered as MTX and 0.4%-11% as 7-OH-MTX. The renal clearance of 7-OH-MTX was in the range of 0.0173 +/- 0.0149 liter/kg/hour. The pharmacokinetics of MTX and 7-OH-MTX was influenced by orally coadministered activated charcoal, presumably by inhibition of enteral reabsorption of MTX and 7-OH-MTX.
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PMID:Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. 695 40

23 patients with osteogenic sarcoma were observed during 142 6-hour high-dose infusions of methotrexate (MTX, 3,000--8,200 mg/m2). Calcium leukovorin was given by intravenous injection at 3-hour intervals beginning 2 h after the completion of each MTX infusion with extension of the intervals to 6 h following the first day of rescue. All patients also received continuous intravenous infusions of alkalinized fluids for the entire duration of leukovorin rescue. No larger doses of leukovorin were given to any patient. Three of the 142 MTX infusions resulted in mild cytotoxic side effects. Plasma MTX clearance ranged from 90 to 600 ml/min among the 62 infusions where plasma clearance could be accurately calculated. The 3 patients with mild toxicity had low drug clearance, but others with similar low MTX clearance experienced no apparent toxic effects beyond the expected transient nausea.
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PMID:High-dose methotrexate with a safe rescue program. 697 32

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.
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PMID:Prognostic factors in the response of primary osteogenic sarcoma to preoperative chemotherapy (high-dose methotrexate with citrovorum factor). 697 39

We treated mice with 89Sr induced osteosarcoma with HD MTX (high-dose methotrexate) and CF (rescue by citrovorum factor), and observed the results of MTX administration. MTX and CF constantly injected through their tail veins at intervals of 6, 24 hours, respectively. The amont of MTX administered ranged from 60 mg/kg to 2,000 mg/kg, while CF administered totalled 200 mg/kg. To determine their antitumor efficacy, we adopted 3H-thymidine based labelling index and mitotic index as well as microautoradiography, and observed how the tumor proliferation had been prohibited. The anti-tumor efficacy was significant when 500 mg/kg of MTX was administered; there was no significant increase in anti-tumor efficacy even after 1,000, 2,000 mg/kg of MTX had been administered. Rather, the tumor was tending to be healed as time passed by after the administration of MTX being 500 mg/kg. Then we administered 500 mg/kg of MTX and 200 mg/kg of CF twice at intervals of 6 days. After we had administered MTX in combination with CF, we started observing the changing condition of the tumor. As a result, we recognized their significant anti-tumor efficacy. The tumor did not show any indication of serious growth. In view of the above, we concluded that it would be more effective to administer repeatedly an optimum dose of MTX and CF than to administer an ultra-high dose of MTX and CF.
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PMID:[Studies on the effect of high-dose methotrexate-citrovorum factor treatment for 89Sr induced osteosarcoma in mice (author's transl)]. 697 19

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.
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PMID:Plasma phenylalanine: tyrosine ratios during high-dose methotrexate-citrovorum "rescue". 698 Oct 54

9 HDMTX infusions with 30 to 55 g MTX and leucovorin rescue were given to 3 patients with multifocal osteosarcoma. Resistance to standard MTX infusions with up to 12 g/m2 body surface in 4 hours indicated the administration of these higher doses (27 g/m2 body surface on average) over a shorter period of time (160 min on average). MTX input was controlled by the increase in plasma MTX levels which were determined by EMIT enzyme assay within a few minutes of sampling. The plasma MTX levels were found to be up to 10 times (average 4 times) higher than those achieved by the standard infusion. All infusions proved to be relatively well tolerated in all 3 cases, although, thrice after 36 hours an increased leucovorin rescue had to be made for 12 hours, because of delayed renal methotrexate excretion; the usual leucovorin rescue (15 mg every 6 hours) was given for an average of five days. No therapeutic effects were seen either clinically, radiologically, or histologically. The resistance to HDMTX in these three patients could not be broken by HDMTX PLRD infusions.
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PMID:[Controlled ultra-high dosage methotrexate therapy in three patients with metastatic osteosarcoma (author's transl)]. 702 Feb 62


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