Analysis of chemotherapy dosage and dosage intensity and survival outcomes of high-grade osteosarcoma patients younger than 40 years

Lingling Sun; Yingjun Li; Hengyuan Li; Jian Zhang; Binghao Li; Zhaoming Ye

doi:10.1016/j.clinthera.2014.02.018

Analysis of chemotherapy dosage and dosage intensity and survival outcomes of high-grade osteosarcoma patients younger than 40 years

Clin Ther. 2014 Apr 1;36(4):567-78. doi: 10.1016/j.clinthera.2014.02.018. Epub 2014 Mar 14.

Authors

Lingling Sun¹, Yingjun Li², Hengyuan Li¹, Jian Zhang¹, Binghao Li¹, Zhaoming Ye³

Affiliations

¹ Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Epidemiology and Health Statistics, School of Medicine, Zhejiang University, Hangzhou, China.
³ Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: [email protected].

PMID: 24636527
DOI: 10.1016/j.clinthera.2014.02.018

Abstract

Background: Chemotherapy is essential for long-term survival of osteosarcoma patients. However, the impact of dosage and dosage intensity (DI) of chemotherapeutic agents on patients with high-grade osteosarcoma is largely unknown.

Objective: The object of this study was to evaluate the influence of these dosage-related variables on treatment outcomes in terms of event-free survival (EFS).

Methods: PubMed was searched for relevant English-language articles. Two reviewers extracted data independently. Sufficient data were presented to calculate the planned total dosage and DI for doxorubicin, cisplatin, ifosfamide, and methotrexate. Univariate analysis and partial regression analysis were performed to determine the association of 5-year EFS and the planned total dosage and DI of each drug.

Results: Seventeen studies comprising 23 trial arms met the inclusion criteria. The analysis recruited a total of 2257 patients. The study period ranged from 1976 to 2006. Using univariate analysis, the planned dosage and DI of methotrexate and ifosfamide correlated with better 5-year EFS (P = 0.001 for methotrexate dosage; P = 0.030 for ifosfamide dosage; P < 0.001 for methotrexate DI; and P = 0.033 for ifosfamide DI). There was a trend toward worse 5-year EFS with increase of doxorubicin DI (P = 0.055). Based on the partial regression analysis, the association of doxorubicin DI and ifosfamide dosage and DI with EFS became no longer statistically significant, and the planned total dosage and DI of methotrexate remained significantly correlated with better 5-year EFS (P = 0.001 and P = 0.004, respectively).

Conclusions: We observed a correlation of higher planned methotrexate total dosage and DI with better treatment outcomes in osteosarcoma patients. The present study showed that methotrexate dosage and DI were important predictors of the clinical outcomes and provided the rationale of high-dosage methotrexate in the context of multi-agent chemotherapy.

Keywords: chemotherapy; dosage intensity; methotrexate; osteosarcoma; survival.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Review

MeSH terms

Adolescent
Adult
Analysis of Variance
Antineoplastic Agents / administration & dosage*
Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
Bone Neoplasms / drug therapy*
Bone Neoplasms / mortality
Bone Neoplasms / pathology
Cisplatin / administration & dosage
Disease-Free Survival
Doxorubicin / administration & dosage
Female
Humans
Ifosfamide / administration & dosage
Male
Methotrexate / administration & dosage
Neoplasm Grading
Osteosarcoma / drug therapy*
Osteosarcoma / mortality
Osteosarcoma / pathology
Treatment Outcome

Substances

Antineoplastic Agents
Doxorubicin
Cisplatin
Ifosfamide
Methotrexate