Role of High dose Methotrexate in

Osteosarcoma - YES
Dr.Jayachandran.P.K.
 Cyclophosphamide - RMS
 VAC
 Doxorubicin – active agent
 Substitution of Act – D with Doxorubicin
 Norman Jaffe  1960s
 Lung mets in 6 months after hemipelvectomy  complete
resolution
 Wataru Sutow and Sullivan
 CONPADRI
 Cyclophosphamide, ONcovin( vincristine), L-Phenylalanine
mustard.  aDRIamycin.
 COMPADRI
 Cyclophosphamide, Oncovin( vincristine), Hd- Mtx, L-
Phenylalanine mustard.  aDRIamycin.
 200 pts
 5yr DFS  41%
 Single agent HD - MTX yielded a 40% disease-free
survival
 Weekly high-dose methotrexate, vincristine and
doxorubicin adjuvant therapy
 46 patients 
 5yr RFS – 59%
 5yr OS – 78%

Goorin AM, et al. Weekly high-dose methotrexate and doxorubicin for osteosarcoma: the Dana-Farber Cancer
Institute/the Children’s Hospital--study III. J Clin Oncol. 1987 Aug 1;5(8):1178–84.

Goorin AM, et al. The Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for
osteosarcoma: Three sequential studies. Cancer Treat Symp. 1986;3:155-159.
 MSKCC T7
 75pts
 Preop and post op  Mtx, Vcr, Dox, BCD
 12yr DFS – 72%

 MSKCC T10
 Rosen
 Mtx + Vcr  Sx 
 GR  Mtx, Dox, BCD
 PR  Dox, CDDP, BCD
 153pts
 5yrs DFS – 72%
COSS 77
 Single arm
 Hd – Mtx (6gm/m2), adriamycin, Cyclophosphamide
 100 pts
 40 months  71 evaluable patients  DFS – 55%

Purfürst C et al, Results of the COSS-77 and COSS-80 studies on adjuvant chemotherapy in osteosarcoma
of the extremities. Klin Pädiatr. 1985 Jun;197(3):233–8.
COSS 80
 Randomized 2 arm study
 Hd – Mtx (12gm/m2), adriamycin + CDDP
 Hd – Mtx (12gm/m2), adriamycin + BCD
 No difference in groups
 Total cohort  at 40 months  115 evaluable patients 
DFS 67%
 Comparing COSS 77 and 80  55% vs 67% (p <0.05) 
dose of Mtx has a important role

Purfürst C et al, Results of the COSS-77 and COSS-80 studies on adjuvant chemotherapy in osteosarcoma
of the extremities. Klin Pädiatr. 1985 Jun;197(3):233–8.
COSS 82
 Ransomised 2 arm study
 Study arm  BCD + M  Sx poor response  AP
 Control arm  AP + M  Sx  poor response  BCD
alternating with IP

Winkler K, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial

(COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol Off J Am Soc Clin
Oncol. 1988 Feb;6(2):329–37
Italian sarcoma group – ISG – OS1 trial
 246 patients
 Arm A – MAP  Sx 
 GR  MAP
 PR  MIAP
 Arm B – MIAP  Sx  MIAP

Ferrari S, et al. Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without
Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1. J Clin
Oncol. 2012 Jun 10;30(17):2112–8.
SSG VIII
 113 pts
 Single arm study
 MAP  SX
 GR  MAP
 PR  IE
 5 yr MFS  63%
 5yr OS  74%
 Favorable prognostic factors
 Tumour volume < 190 ml
 24-h serum methotrexate > 4.5 microM
 female gender
 Etoposide/Ifosfamide replacement combination did not improve outcome in
the poor histological responders
Smeland S, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome
and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer Oxf Engl
1990. 2003 Mar;39(4):488–94.
SSG XIV.
 2001–2005; SSG
 71 pts  63 eligible pts.

Smeland S, et al. Results of the Scandinavian Sarcoma Group XIV protocol for classical osteosarcoma. Acta
Orthop. 2011 Apr;82(2):211–6.
 MFS at 5 years  69%,
 EFS at 5 yrs  65%
 OS at 5yrs 77%
 Limb salvage procedure rate  90%
 Local recurrence rate  3%

Smeland S, et al. Results of the Scandinavian Sarcoma Group XIV protocol for classical osteosarcoma. Acta
Orthop. 2011 Apr;82(2):211–6.
Rizzoli Institute IOR – OS1 study
 1983 to 1986, the first neo-adjuvant study
 127 patients
 Randomized to receive either a moderate (750 mg/m2) or high
(7.5 g/m2) dose of methotrexate added to cisplatin, doxorubicin
and bleomycin, cyclophosphamide and dactinomycin.
 Cisplatin was intra-arterially delivered.
 12-year DFS was 46% (high dose methotrexate 52%, moderate
dose 38%)
 Multivariate analysis  significant advantage for patients
treated with high dose methotrexate.

Ferrari S, et al. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of
the extremity treated with neoadjuvant chemotherapy. Ann Oncol. 1997;8:765-771.
Rizzoli Institute IOR – OS2 study
 1986 to 1989
 Doxorubicin was added to methotrexate and intra-arterially
delivered cisplatin  Sx
 poor responder  ifosfamide in addition to methotrexate,
cisplatin and doxorubicin.
 164 patients.
 Good histologic response  71%,
 5-year DFS  65%
 5-year OS  74%
 Good responder  5-year DFS - 67%,
 Poor responder  5-year DFS - 51% (p = 0.08)

Bacci G, et al. Long-Term Outcome for Patients With Nonmetastatic Osteosarcoma of the Extremity Treated at
the Istituto Ortopedico Rizzoli According to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 Protocol: An
Updated Report. J Clin Oncol. 2000 Dec 15;18(24):4016–27.
INT 0133 – intergroup study
 2x2 factorial design
 Regimen A  MAP
 Regimen A+  MAP + MTP
 Regimen B  MAP + I
 Regimen B+  MAP + I + MTP

Meyers PA, et al. Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl
Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005 Mar 20;23(9):2004–11.
Meyers PA, et al. Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl
Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005 Mar 20;23(9):2004–11.
Meyers PA, et al. Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl
Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005 Mar 20;23(9):2004–11.
EURAMOS – 1
 2#MAP  Sx
 Good response -
 2#MAP 2#MA
 2#MAP  2#MA  2#IFN
 Poor response
 2#MAP 2#MA
 MAP/IE for 7 cycles

Whelan JS, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-
randomisation treatment. Ann Oncol. 2014 Nov 24;mdu526.
Whelan JS, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-
randomisation treatment. Ann Oncol. 2014 Nov 24;mdu526.
 716 were ramdomised in GR arm
 MAP  359  3yr EFS 74%
 MAP+ IFN  357  3yr EFS 77%
 P=0.21

Bielack SS,et al. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-
2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to
Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol.
2015 Jun 1;JCO.2014.60.0734.
 618  Randomised In Poor responders
 MAP  310  3yr EFS 60%
 MAP/IE 308  3yr EFS 57%
 P= 0.8
 More Gr3/4 febrile neutropenia and thrombocytopenia in
MAP/IE group
 More non hematological toxicity in MAP/IE group.

Marina NM et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative
chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international,
randomised controlled trial. Lancet Oncol. 2016 Aug 25;
Why YES
 All protocols designed  most of them incorporate
HDMTX
 Time tested therapy in Osteosarcoma
 Still the newer trials also incorporate HD – MTX as a part
of protocol
 No major proven toxicities of HDMTX as it is.
 THANK YOU…
I welcome Dr.Manu to speak against HDMTX
 REBUTTAL
EORTC 80831 – EO1 Study
 The conclusion of this study was that both treatment arms
were tolerable with no difference in toxicity
 DFS was better for 2 drug regimen without methotrexate.
 It was however, not a true comparison of addition of MTX
as total doase and dose intensity in two arms are
substantially different.
 Those randomised in 3 drug arm recieveed only 66% of
CDDP and DOX
 Final conclusion of this study is that total dose and dose
intensity are important predictors
Bramwell VH, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable
osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma
Intergroup. J Clin Oncol Off J Am Soc Clin Oncol. 1992 Oct;10(10):1579–91.
EORTC 80831 – EO1 study

Bramwell VH, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable
osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma
Intergroup. J Clin Oncol Off J Am Soc Clin Oncol. 1992 Oct;10(10):1579–91.