Cochrane Database of Systematic Reviews

Methotrexate for high-grade osteosarcoma in children and

young adults (Review)

van Dalen EC, van As JW, de Camargo B

van Dalen EC, van As JW, de Camargo B.

Methotrexate for high-grade osteosarcoma in children and young adults.
Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD006325.
DOI: 10.1002/14651858.CD006325.pub3.

www.cochranelibrary.com

Methotrexate for high-grade osteosarcoma in children and young adults (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Methotrexate for high-grade osteosarcoma in children and

young adults

Elvira C van Dalen1 , Jorrit W van As2 , Beatriz de Camargo3

1 Department of Paediatric Oncology, Emma Children’s Hospital/ Academic Medical Center, Amsterdam, Netherlands. 2 c/o Cochrane
Childhood Cancer Group, Emma Children’s Hospital / Academic Medical Center, Amsterdam, Netherlands. 3 Pediatric Hematology-
Oncology Program, Centro de Pesquisa, Instituto Nacional do Cancer, Rio de Janeiro, Brazil

Contact address: Elvira C van Dalen, Department of Paediatric Oncology, Emma Children’s Hospital / Academic Medical Center, PO
Box 22660 (room TKsO-247), Amsterdam, 1100 DD, Netherlands. e.c.vandalen@amc.uva.nl.

Editorial group: Cochrane Childhood Cancer Group.

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2012.

Citation: van Dalen EC, van As JW, de Camargo B. Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane
Database of Systematic Reviews 2011, Issue 5. Art. No.: CD006325. DOI: 10.1002/14651858.CD006325.pub3.

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
The majority of the currently used treatment protocols for osteosarcoma 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.
Objectives
To compare the effectiveness of treatment including MTX with treatment without MTX for children and young adults (up to 21 years)
with primary high-grade osteosarcoma.
Search methods
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 4, 2010), MEDLINE (1966 to January
2011) and EMBASE (1980 to January 2011). In addition, we searched reference lists of relevant articles, conference proceedings and
ongoing trials databases.
Selection criteria
Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of treatment including MTX with
treatment without MTX in the treatment of paediatric high-grade osteosarcoma.
Data collection and analysis
Two reviewers independently performed the study selection. One reviewer performed the data extraction and quality assessment, which
was checked by another reviewer.
Main results
We could not identify any studies in which the only difference between the treatment groups was the use of MTX.
We did identify a RCT comparing MTX with cisplatin (n=30 children). 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
Methotrexate for high-grade osteosarcoma in children and young adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
groups was identified (RR=0.44; 95% CI 0.17 to 1.13; P=0.09). A significant difference in the occurrence of toxicities in favour of
MTX was identified, but with regard to quality of life treatment with cisplatin seemed to give better results.
For other combinations of treatment including and not including MTX no studies were identified.
Authors’ conclusions
Since no RCTs or CCTs in which only the use of MTX differed between the treatment groups were identified, no definitive conclusions
can be made about the effects on antitumour efficacy, toxicities and quality of life of the addition of MTX to treatment of children
and young adults with primary high-grade osteosarcoma. The same is true for combinations of treatment including and not including
MTX other than treatment with MTX versus treatment with cisplatin. Only 1 RCT comparing MTX with cisplatin treatment was
available and therefore, no definitive conclusions can be made about the effectiveness of these agents in children and young adults with
primary high-grade osteosarcoma. Furthermore, this study was performed in a different treatment era. Nowadays single agent treatment
of osteosarcoma is considered inadequate. Based on the currently available evidence, we are not able to give recommendations for the
use of MTX in clinical practice. More high quality research is needed.

PLAIN LANGUAGE SUMMARY

Methotrexate for high-grade osteosarcoma in children and young adults
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.

Methotrexate for high-grade osteosarcoma in children and young adults (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.