HD METHOTREXATE IN

OSTEOSARCOMA

AGAINST
• 5-year OS of localized disease over the past 40 years: from 5% - 10%
(in historical controls) to 65% - 75%
• Doxorubicin, cisplatin, high-dose methotrexate and ifosfamide
• HD MTX old drug and debatable role
• Toxicity and need of monitoring
Why so much concern ?
• Chemoresistance
• 8 g -12 g /m2
• 4-6 hours
• LV rescue
• Hospitalisation
• Monitoring
• Toxicity
• Cost of treatment
Cochrane review Methotrexate for high-grade osteosarcoma in
children and young adults- 2011

• No RCTs or CCTs
• No conclusions

• One RCT comparing CDDP Vs MTX (n=30)

• Similar RR
• No data on OS/RFS
• Cisplatin better quality of life
OS 99 trial

• 12 cycles of chemotherapy over 35 weeks

• 3 cycles of carboplatin,ifosfamide and one cycle of doxorubicin
before resection, followed by 2 additional cycles of
carboplatin/ifosfamide and 3 cycles each of combined with
ifosfamide or carboplatin.

• Frontline treatment of localized osteosarcoma without methotrexate: results of the St.

Jude Children's Research Hospital OS99 trial.Cancer. 2011 Jun 15.
• 72 eligible patients.
• Forty of the 66 (60.6%) - (> 90% tumor necrosis)
• The estimated 5-year EFS was 66.7% ± 7.0% ( 66.0% ± 6.8% for OS91)
• Estimated 5-year survival was 78.9% ± 6.3% for (74.5% ± 6.3% for
OS91 )
• Well tolerated regime,OPD basis
EOI ( European Osteosarcoma Intergroup)
• Bramwhell et al 1992
• EOI BO02/80831
• AP (3 weekly) vs AP +/- 8g/m2 MTX 10 days prior to AP
• 3/2 Cycles followed by surgery
• N=99,
• DFS 57% Vs 41%
• Dose intensity
• From Germany
• 53 patients,12 year follow up
• ADR/CDDP/CTx and VCR
• OS – 5 Y- 71.7%.10 Year OS- 67.2%
• 73% Vs 63% – Responders Vs Non responders

• PU Tunn, P Reichardt - Oncology Research and Treatment, 2007 - karger.com

• Adriamycin with HD MTx ( 2g/m2) Vs Moderate dose (200mg/m2)
• DFS 55% Vs 50%
• No difference
• Bacci et al

• Adriamycin-methotrexate high dose versus adriamycin-methotrexate moderate dose as

adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study.Eur J
Cancer Clin Oncol. 1986 Nov 22(11):1337-45
• J Bajpayi et al TMH

• 36 patients
• IAP chemotherapy
• OS ,PFS 95% , 70% at 2.2 years
• Histological response 67%
• Pathak et al
• 50 patients
• 6 x AP - Adjuvant
• RFS 72%, OS 69%

• Pathak AB, Advani SH, Iyer RS et al. Adjuvant chemotherapy for osteogenic sarcoma of
the extremity with sequential adriamycin and cisplatin. J SurgOncol. 1993;52:181-4
SECOND LINE SETTING
• St Jude experience
• Leary et al Cancer July 2013
• 110 patients (1970-2004)
• 10 year PREFS and PROS 11.8% and 17%
• With chemotherapy (Cisplatin,ADR,MTx,HLX) Median PREFS- 3.5
months and PRS-8.2 months
 chemo No chemo
CR1 16 46
PREFS 10Y 16.7% 34.8
PROS 12.5% 24%
Any Relpase 39 23
PREFS 11% 60%
PROS 5% 47%
• COSS Analysis – 576 patients
• Time to relapse , tumour burden ,Surgery important factors
• 381 pts had chemo, 88% got combination chemotherapy
• 53 patients had HDMTx in R1 and 37 in R2
• No advantage
Non HD MTx based regimens are preferred option in localised
osteosarcoma in first line setting

In second line setting evidence for chemotherapy itself is doubtful and

there is no specific role for HD MTx.