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)

Subacute transient cerebral dysfunction following high-dose methotrexate occurred during neo-adjuvant chemotherapy for an eighteen-year-old male with osteosarcoma in his right femur. The variety of symptoms including hemiparesis and hesitancy of speech occurred 8 days after an administration of high-dose methotrexate (10 g/m2). Evaluations including CT scan of the brain, hemogram and blood chemistry revealed no abnormal findings. The patient found it difficult to sit, speak and eat, but was not confused. He improved in a few days without any specific treatment or residual sequelae. This syndrome was transient and did not recur when he had two additional HD-MTX treatments. The cause of this syndrome remains unknown and does not seem to be predictable. It is, thus, necessary for oncologists to take due care with regard to this syndrome in HD-MTX chemotherapy.
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PMID:[A case of subacute transient cerebral dysfunction in a osteosarcoma patient following high-dose methotrexate]. 1191 42

The authors evaluated their ability to maintain planned dosing schedules for high-dose methotrexate (HD-MTX) in patients with nonmetastatic osteosarcoma. Twenty-seven patients who received therapy according to 2 POG protocols (8651 and 9351), both of which included HD-MTX (12 g/m(2)/week for 2 consecutive weeks), between 1988 and 1998 were studied. Significantly fewer HD-MTX infusions were given on the second week to patients treated on POG 9351 (33 vs. 93%; p < .0001). The hydration guidelines were identical and there was no difference in peak serum MTX levels either within or between protocols. Differences in the administration of combination chemotherapy in 9351 compared to 8651 may have contributed to the increased toxicity associated with HD-MTX on 9351, although this is speculative. The use of HD-MTX should be carefully planned so that it does not decrease its dose intensity or that of other effective agents.
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PMID:Variability in dose intensity of high-dose methotrexate for nonmetastatic osteosarcoma. 1221 94

High-dose methotrexate (HDMTX) is a component of many cancer treatment regimens. Despite careful management, delayed renal clearance, followed by extremely high serum levels with potentially life-threatening toxicity can occur. In the present study, we report our results of carboxypeptidase-G2 (CPDG2) rescue in 8 patients with delayed methotrexate elimination and renal impairment after HDMTX therapy for lymphoma or osteosarcoma. A dose of 50 U/kg CPDG2 was administered. MTX plasma levels decreased rapidly and recovery of renal function was observed in all patients. No patient developed severe WHO grade 4 MTX toxicity. CPDG2 provides an alternative route of MTX elimination by converting it to inactive and non-toxic metabolites. CPDG2 rescue was well tolerated, safe and very effective in preventing severe or life-threatening MTX toxicity.
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PMID:Carboxypeptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy. 1253 39

We retrospectively studied 790 patients with osteosarcoma treated by neoadjuvant chemotherapy at a single institution between 1983 and 2000 according to different protocols, all including a high dose of methotrexate (HDMTX), to determine the incidence of delayed clearance of HDMTX, and identify patients at high risk for this kind of toxicity. Chemotherapy was administered according to 7 different protocols, successively activated, in which HDMTX was associated with other drugs (cisplatin, adriamycin, ifosfamide) in different combinations. The doses of MTX ranged between 7.5 to 12 g/m(2) and patients received from 1 to 10 cycles with MTX for a total number of 4219 cycles. The incidence of delayed clearance of MTX (plasma values of the drug at 24 h >5 microM/l) was 8.6% per patient and 1.6% per cycle of treatment. In 51 cases the delayed clearance of MTX was "mild" (plasma values of MTX at 24 h between 5 and 19 microM/l) and in 18 cases "severe" (plasma values of MTX at the 24 h >20 microM/l). The delayed clearance of MTX was significantly correlated with the age of patients (16% for patients over 20 vs. 6% for younger patients: p=0.0001) and was significantly more frequent during the first cycles of chemotherapy (7% during the first 3 cycles of treatment vs. 2% during subsequent cycles). There was also a significant correlation (p=0.0001) between the plasma values of MTX at the end of the infusion and at 18 h and the delayed clearance of the drug. In addition to support treatment by increased hydration and sodium bicarbonate, all patients who experienced the delayed clearance of MTX were treated solely with a high dose of leucovorin (HDLV), which was started at the first 18 h. Significant neutropenia and/or thrombocythopenia, increase of serum creatinine, mucositis of varying degrees and vomiting occurred in most cases of severe delayed clearance of MTX, but all patients completely recovered. We conclude that in spite of adequate hydration and urine alkalinization and the use of pharmacokinetically guided leucoverin rescue, delayed clearance of MTX may still occur and that its incidence is higher in older patients and during the first cycles of treatment. However, if "rescue" treatment is started early, the consequent morbility is tolerable and these patients can be rescued using only HDLV, without the need for extracorporeal removal.
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PMID:Delayed methotrexate clearance in osteosarcoma patients treated with multiagent regimens of neoadjuvant chemotherapy. 1279 34

High dose methotrexate (HDMTX) with folinic acid rescue is widely used to treat osteosarcoma, which predominantly afflicts children; the study investigated HDMTX pharmacokinetics (pk) in adult subjects in neoadjuvant/adjuvant settings. Twenty five patients with advanced osteosarcoma (11 females--14 males, median age 26.0 years) were treated by 12 g/m2 HDMTX 4 hour iv infusion (64 total courses, range 1-7 courses). Pk was determined by non-compartmental analysis and population pk modeling. Median (range) bioavailability pk parameters were: C(max) (maximum MTX concentration) 1149.5 microM (692-2,200), AUC(tot) (total area under curve) 6,955.1 micromol*h/l (3,477-12,681). C(max)>1,000 microM gave increased histological responses (p < 0.05). Six covariates (height-weight-hemoglobin-AST-ALT-creatinine) were found to influence MTX volume of distribution (V) and elimination rate constant (K(el)). Toxicity was mild: only two reversible G4 events were observed, related to AUC(tot) >12,000 micromol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between C(max)/AUC(tot) and subject age/sex was found, even in the population pk model. The excretion mechanism is not affected by sex/age differences. HDMTX can safely be administered to adults: as in younger patients, a good clinical response can be predicted by C(max), while severe toxicity depends on highest AUC(tot) values.
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PMID:High dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results. 1612 May 50

Oral mucositis is a major toxicity associated with high-dose methotrexate (HD-MTX) therapy in the treatment of children with acute lymphoblastic leukaemia and osteosarcoma. This pilot matched case-control study investigated the associations between plasma concentration of MTX at 42 (p-MTX(42h)) and 66 (p-MTX(66h)) h, absolute neutrophil count (ANC) < or = or >1.0 x 10(9)/l, serum transaminases (ASAT/ALAT) < or > or =58 U/l, WHO < or > or =grade 2 nausea/vomiting and WHO < or > or =grade 2 oral mucositis. In this study, 11 children with WHO > or =grade 2 oral mucositis were compared with 17 control children matched for age, diagnosis and MTX-dosage. The results indicated that children with p-MTX(42h) > or = 1.0 micromol/l had an odds ratio (OR) of 4.3 of developing oral mucositis when compared with the referent group of children who had p-MTX(42h) < 1.0 micromol/l. Children with p-MTX(66h) >= 0.2 micromol/l had an OR of 8.2 of developing oral mucositis when compared with the referent group of children who had p-MTX(66h) < 0.2 micromol/l. Children with ANC < or = 1.0 x 10(9)/l had an OR of 1.2 of developing oral mucositis when compared with the referent group of children who had ANC > 1.0 x 10(9)/l. In comparison with the referent group of children, who had <58 U/l ASAT/ALAT, those with ASAT/ALAT > or = 58 U/l had an OR of 1.2 of developing oral mucositis. Finally, children with WHO grade > or =2 nausea/vomiting had an elevated risk of developing oral mucositis when compared with the referent group of children who had WHO grade <2 nausea/vomiting (OR = 8.7). In conclusion, the results in this preliminary study provide support for the hypothesis that the risk of oral mucositis is associated with the plasma MTX concentration at 66 h and the level of nausea/vomiting.
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PMID:Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer. 1841 35

Preoperative high-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is still a mainstay in the treatment of osteosarcoma. This anticancer agent is characterized by a narrow therapeutic index and wide interpatients variability. To ensure effective and safe administration of HD-MTX, we had earlier developed an adaptive-dosing schedule with a feedback strategy. In our institute, the MTX dosage was tailored according to individual pharmacokinetics parameters, determined in real time both from two blood samples (3.5 and 4.5 h) and from Bayesian population parameters. Up to 20 g of MTX was safely administered as 8-h infusions. Low MTX elimination rate has, however, been reported in 15-20% of the patients, and forecasting the MTX elimination phase and the management of leucovorin rescue is still a challenging issue in clinical oncology. This study aims at identifying the clinical or biological covariates related to impaired MTX clearance, and at validating a new limited sampling strategy (LSS), allowing for the accurate prediction of the MTX terminal elimination phase. This retrospective study was carried out on 49 patients (30 men, 19 women; mean age, 26.7 years) treated for osteosarcoma with HD-MTX. The population and individual pharmacokinetics parameters were computed, before the identification of the relevant covariates. Different LSSs were then tested, to predict accurately when the MTX plasma concentrations would drop below 0.2 micromol/l, the threshold associated with the end of the rescue of leucovorin with alkaline hydration. Two main covariates (creatinemia clearance and alanine aminotransferase) were correlated with MTX clearance. Conversely, the impact of body surface area on MTX pharmacokinetics was weak, suggesting that dosing schedules based on body surface area were inadequate and potentially hazardous. A new LSS predicting accurately when the MTX concentration would reach 0.2 micromol/l has been validated; blood samples are stopped as soon as the MTX concentration drops to 1 micromol/l. With this LSS, our retrospective study suggests that 60% of the patients would have left the hospital earlier than they actually did owing to a better forecasting of the MTX decrease, thus improving their quality of life while improving the cost-effectiveness for the institute. HD-MTX can be administered safely using an adaptive-dosing strategy with drug monitoring. Moreover, pharmacokinetic modeling permits the accurate forecasting of the MTX elimination profile, thus allowing for a better management of the postinfusion care of cancer patients treated with particularly high doses of this drug.
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PMID:High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy. 1851 Jan 72

The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.
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PMID:Population pharmacokinetics of high-dose methotrexate after intravenous administration in pediatric patients with osteosarcoma. 1907 31

The influence of age and sex on chemotherapy-related toxicity was evaluated in children and adults with non metastatic osteosarcoma. treatment consisted of methotrexate (MTX, 12 g/m(2)), cisplatin (CDP 120 mg/m(2)) and doxorubicin (ADM 75-90 mg/m(2)) and high-dose ifosfamide (HDIFO). toxicity data from 1,051 courses (295 with MTX, 756 based on doxorubicin, cisplatin and high-dose ifosfamide) were analyzed. Children (4-14 yrs) and females showed a higher incidence of grade 4 neutropenia and thrombocytopenia and were more frequently hospitalized for neutropenic fever compared to adolescents and young adults (AYA, 15-19 yrs) and adults (>20-40 yrs). Delayed MTX excretion was higher in adults than AYA and children. Adults (up to 40 years) can be treated with pediatric protocols for osteosarcoma and they experience lower hematologic toxicity compared to pediatric population. further investigations on sex-related susceptibility to chemotherapy in osteosarcoma patients are recommended.
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PMID:Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma. 1942 75

Strategies effective for accelerating methotrexate removal in delayed methotrexate excretion have not been universally accepted. The authors report a case of a 12-year-old girl with osteosarcoma who developed acute renal failure immediately after the first administration of high-dose methotrexate. Plasma methotrexate was effectively removed with repeated charcoal hemoperfusion in addition to plasma exchange and leucovorin rescue. Charcoal hemoperfusion was most effective for reducing plasma methotrexate with approximately 50% of methotrexate being reduced during each of the procedures. No rebound increase in MTX levels was observed. The patient received further therapy with other cancer drugs and has been well for 3.5 years.
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PMID:Effect of charcoal hemoperfusion for removal of plasma methotrexate in a patient with acute renal failure. 1986 8


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