No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma

Bacci, Gaetano; Loro, Loretta; Longhi, Alessandra; Bertoni, Franco; Bacchini, Patrizia; Versari, Michela; Picci, Piero; Serra, Massimo

doi:10.1097/01.cad.0000203379.14738.d9

Cited by 14 publications

(5 citation statements)

References 14 publications

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“…Here, as well, the low sample size would explain the discrepancies with Tunn/Reichardt other studies [30]. Bacci et al [31] showed that an increasing dose of MTX increases the MTX serum peaks, but does not correlate with the histologic response of the tumor. Furthermore, Crews et al [32] proved that very high MTX exposures were associated with a poor outcome.…”

Section: Discussioncontrasting

confidence: 51%

Chemotherapy for Osteosarcoma without High-Dose Methotrexate: A 12-Year Follow-Up on 53 Patients

Tunn

Reichardt²

2007

Oncol Res Treat

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The clinical relevance of polychemotherapy in osteosarcoma is undisputed and well proven. In this retrospective study we report the results of chemotherapy treatment without high-dose methotrexate (HDMTX) for osteosarcoma. Patients and Methods: Between 1986 and 1992, 53 patients with stage IIB extremity osteosarcoma received multimodal therapy (age: 6-36 years, median 17 years). All patients received neoadjuvant and adjuvant chemotherapy with adriamycin, cisplatin, cyclophosphamide, and vincristine without HDMTX. In 60.4%, tumor volume was =150 ml and in 39.6% >150 ml. Surgical modalities were distributed as follows: 71.7% of patients received limb-sparing surgery, 20.8% ablative surgery, and 7.5% rotationplasty. 35.8% of patients developed pulmonary metastases. Results: Overall survival (OAS) was 71.7% after 5 years and 67.2% after 10 years. Ten-year OAS was not observed with local recurrences; without local recurrence 10-year OAS was 74.2% (p = 0.002). Five-year OAS was 31.6% in patients who developed pulmonary metastases. Ten-year OAS was 71.1% and 61.1% when tumor volume was =150 ml and >150 ml, respectively (p = 0.445). Ten-year OAS was 73.5% in responders to preoperative chemotherapy; in poor responders 62.1% (p = 0.353). Event-free 10-year survival was 70.8% in responders and 48.3% in poor responders (p = 0.099). Conclusion: Compared to treatment protocols including HDMTX similar survival rates were achieved.

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Section: Discussioncontrasting

confidence: 51%

Chemotherapy for Osteosarcoma without High-Dose Methotrexate: A 12-Year Follow-Up on 53 Patients

Tunn

Reichardt²

2007

Oncol Res Treat

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“…Several studies have demonstrated that the response to HD-MTX is correlated with the delivered dose and the serum level of MTX, thus stressing the need for developing adaptivedosing methods [3,4,6,21]. Our institute has developed over the past decade Bayesian, dynamic adaptive dosing with feedback methods, which can be applied to various anticancer drugs such as CDDP, CBDCA, etoposide and MTX [11,[22][23][24].…”

Section: Discussionmentioning

confidence: 98%

High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy

Dupuis¹,

Mercier²,

Yang³

et al. 2008

Anti-Cancer Drugs

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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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“…Wide inter- and intra-variability in serum methotrexate levels has been observed following high-dose methotrexate (8–12 g/m 2 ) 19 . Higher serum methotrexate levels have been linked with better survival 20,21 but results have been inconsistent, with others finding no difference or even poorer survival, with peak concentrations >1500 μM 22 .…”

Section: Discussionmentioning

confidence: 99%

Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: A report from the European Osteosarcoma Intergroup

McTiernan¹,

Jinks²,

Sydes³

et al. 2012

European Journal of Cancer

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AimChemotherapy-induced toxicity is an independent prognostic indicator in several cancers. We aimed to determine whether toxicity was related to survival and histological response in high-grade localised extremity osteosarcoma. We undertook a retrospective analysis of patients treated within three consecutive randomised controlled trials (RCTs) of the European Osteosarcoma Intergroup.MethodsBetween 1982 and 2002, 533 patients were randomised to six cycles of doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. Toxicity data were collected prospectively and graded according to the World Health Organisation (WHO) criteria. Standard univariate and multivariate models were constructed to examine the relationship between reported toxicity, survival, and histological response.ResultsFive- and 10-year overall survival was 57% (95% confidence interval (CI) 52–61%) and 53% (49–58%), respectively. Grades 3–4 oral mucositis (hazard ratio (HR) 0.51, 95% CI 0.29–0.91), grades 1–2 nausea/vomiting (HR 0.37, 95% CI 0.16–0.85), grades 1–2 thrombocytopenia (HR 0.49, 95% CI 0.27–0.87), good histological response (HR 0.42, 95% CI 0.27–0.65), and distal tumour site (HR 0.45, 95% CI 0.28–0.71) were associated with improved survival in multivariate analysis. The only factors that were independently associated with histological response were older age (odds ratio (OR) 0.18, 95% CI 0.04–0.72) and chondroblastic tumour (OR 0.28, 95% CI 0.10–0.77), both being associated with a significantly lower chance of achieving a good response.ConclusionChemotherapy-induced toxicity predicts survival in patients with localised extremity osteosarcoma. Investigation of the pharmacogenomic mechanisms of constitutional chemosensitivity underlying these observations will present opportunities for personalising treatment and could lead to improved outcomes.

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No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma

Cited by 14 publications

References 14 publications

Chemotherapy for Osteosarcoma without High-Dose Methotrexate: A 12-Year Follow-Up on 53 Patients

Chemotherapy for Osteosarcoma without High-Dose Methotrexate: A 12-Year Follow-Up on 53 Patients

High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy

Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: A report from the European Osteosarcoma Intergroup

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