As a result of the introduction of chemotherapy, the survival of children with osteosarcoma has improved dramatically. The majority of the currently used treatment protocols are based on a combination of doxorubicin, cisplatin, methotrexate (MTX) and/or ifosfamide, of which MTX seems to be one of the most active drugs. However, in the literature, this has not been unambiguously proven. A well-informed decision on the use of MTX in the treatment of children and young adults diagnosed with primary high-grade osteosarcoma should be based on high quality evidence on both antitumour effects and adverse effects.

This systematic review focused on (randomised) controlled studies. The authors found that there were no studies in which the only difference between the intervention and control group was the use of MTX. They did identify a RCT comparing MTX with cisplatin. The risk of bias in this study was difficult to assess due to a lack of reporting. Survival could not be evaluated, but no evidence of a significant difference in response rate between the treatment groups was identified. However, a significant difference in the occurrence of toxicities in favour of treatment with MTX was identified, but treatment with cisplatin seemed to give better results with regard to quality of life. It should be noted that this study was performed in a different treatment era. Nowadays single agent treatment of osteosarcoma is considered inadequate. For other combinations of treatment including and not including MTX no studies are available. More high quality research is needed. At the moment, the authors are awaiting more details on 5 studies for which the currently available data were insufficient to assess eligibility for inclusion in this review.