Abstract
Purpose
High-dose methotrexate (HD-MTX) with leucovorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacokinetic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity.
Methods
Pharmacokinetic data of 105 patients with osteosarcoma treated with 989 HD-MTX courses were evaluated. Pharmacokinetic parameters (clearance, half-life and AUC) were calculated based on methotrexate (MTX) serum levels measured at 6, 24, 36, 48 h after the initiation of the infusion. Clinical data were collected by retrospective chart review. Hepato-, nephro- and bone marrow toxicity parameters were categorized according to Common Toxicity Criteria v.3.0, and MTX dose intensity was calculated. Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan–Meier method.
Results
Patients with serious hepatotoxicity had higher mean peak MTX concentrations (p < 0.0001), 24-h (p = 0.001) and 48-h MTX serum levels (p = 0.008) and AUC0–48 (p < 0.0001), and lower MTX clearance (p = 0.0002). No significant association was found between toxicity and age, gender, presence of metastases or histological tumor response. Patients with higher 48-h MTX serum levels had significantly better OS and EFS. Higher dose intensity was associated with better EFS (p = 0.0504). There was no association between presence of toxicity and survival.
Conclusion
There was correlation between MTX exposure and the incidence of toxicity. Higher serum concentrations at 48 h were associated with a better 5-year OS and EFS. These results suggest that higher MTX exposure may lead to serious side effects, but it also improves treatment outcome.
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References
Aquerreta I, Aldaz A, Giraldez J, Sierrasesumaga L (2004) Methotrexate pharmacokinetics and survival in osteosarcoma. Pediatr Blood Cancer 42(1):52–58. doi:10.1002/pbc.10443
Bacci G, Picci P, Avella M, Dallari D, Ferrari S, Prasad R, Di Scioscio M, Malaguti C, Caldora P (1990) The importance of dose-intensity in neoadjuvant chemotherapy of osteosarcoma: a retrospective analysis of high-dose methotrexate, cisplatinum and adriamycin used preoperatively. J Chemother 2(2):127–135
Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M, Bacchini P, Brach del Prever A, Tienghi A, Comandone A, Campanacci M (1998) Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol 16(2):658–663
Bacci G, Ferrari S, Longhi A, Forni C, Giacomini S, Lari S, Versari M (2001) Relationship between dose-intensity of treatment and outcome for patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Oncol Rep 8(4):883–888
Bacci G, Loro L, Longhi A, Bertoni F, Bacchini P, Versari M, Picci P, Serra M (2006) No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs 17(4):411–415. doi:10.1097/01.cad.0000203379.14738.d9
Bielack S, Jurgens H, Jundt G, Kevric M, Kuhne T, Reichardt P, Zoubek A, Werner M, Winkelmann W, Kotz R (2009) Osteosarcoma: the COSS experience. Cancer Treat Res 152:289–308. doi:10.1007/978-1-4419-0284-9_15
Bieling P, Bielack S, Delling G, Jurgens H, Kotz R, Dose C, Astheimer H, Exner G, Gadner H, Graf N et al (1991) Neoadjuvant chemotherapy of osteosarcoma. Preliminary results of the cooperative COSS-86 osteosarcoma study. Klin Padiatr 203(4):220–230. doi:10.1055/s-2007-1025433
Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41(1):36–51
Bleyer WA (1989) New vistas for leucovorin in cancer chemotherapy. Cancer 63(6 Suppl):995–1007
Comandone A, Passera R, Boglione A, Tagini V, Ferrari S, Cattel L (2005) High dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results. Acta Oncol 44(4):406–411. doi:10.1080/02841860510029770
Crews KR, Liu T, Rodriguez-Galindo C, Tan M, Meyer WH, Panetta JC, Link MP, Daw NC (2004) High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma. Cancer 100(8):1724–1733. doi:10.1002/cncr.20152
Delepine N, Delepine G, Cornille H, Brion F, Arnaud P, Desbois JC (1995) Dose escalation with pharmacokinetics monitoring in methotrexate chemotherapy of osteosarcoma. Anticancer Res 15(2):489–494
Delepine N, Delepine G, Bacci G, Rosen G, Desbois JC (1996) Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma. Analysis of the literature. Cancer 78(10):2127–2135. doi:10.1002/(SICI)1097-0142(19961115)78:10<2127:AID-CNCR13>3.0.CO;2-0
Graf N, Winkler K, Betlemovic M, Fuchs N, Bode U (1994) Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 12(7):1443–1451
Hegyi M, Semsei AF, Jakab Z, Antal I, Kiss J, Szendroi M, Csoka M, Kovacs G (2011) Good prognosis of localized osteosarcoma in young patients treated with limb-salvage surgery and chemotherapy. Pediatr Blood Cancer 57(3):415–422. doi:10.1002/pbc.23172
Holmboe L, Andersen AM, Morkrid L, Slordal L, Hall KS (2011) High-dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. Br J Clin Pharmacol. doi:10.1111/j.1365-2125.2011.04054.x
Jaffe NTD (1975) Toxicity of high-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother Rep 6:31–36
Jaffe N, Gorlick R (2008) High-dose methotrexate in osteosarcoma: let the questions surcease–time for final acceptance. J Clin Oncol 26(27):4365–4366. doi:10.1200/JCO.2007.14.7793
Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ (2009) Osteosarcoma. J Am Acad Orthop Surg 17(8):515–527.
Schmiegelow K, Pulczynska M (1990) Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia. Br J Cancer 61(5):767–772
Schmiegelow K, Schroder H, Pulczynska MK, Hejl M (1989) Maintenance chemotherapy for childhood acute lymphoblastic leukemia: relation of bone-marrow and hepatotoxicity to the concentration of methotrexate in erythrocytes. Cancer Chemother Pharmacol 25(1):65–69
Smeland S, Muller C, Alvegard TA, Wiklund T, Wiebe T, Bjork O, Stenwig AE, Willen H, Holmstrom T, Folleras G, Brosjo O, Kivioja A, Jonsson K, Monge O, Saeter G (2003) Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 39(4):488–494
Von Hoff DD, Penta JS, Helman LJ, Slavik M (1977) Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treat Rep 61(4):745–748
Zelcer S, Kellick M, Wexler LH, Shi W, Sankaran M, Lo S, Healey J, Huvos AG, Meyers PA, Gorlick R (2005) Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer 44(7):638–642. doi:10.1002/pbc.20314
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We are grateful to all the nurses, doctors and patients who took part in the study.
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There are no competing financial interests in relation to the work described.
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Marta Hegyi and Ágnes Gulácsi contributed equally to this work and are co-first authors.
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Hegyi, M., Gulácsi, Á., Cságoly, E. et al. Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma. J Cancer Res Clin Oncol 138, 1697–1702 (2012). https://doi.org/10.1007/s00432-012-1214-2
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DOI: https://doi.org/10.1007/s00432-012-1214-2