Publication de Nicole Delepine : Long-term results of comprehensive treatment for non-metastatic primary limb high-grade osteosarcoma. Emphasis of escalating high dose methotrexate (HDMTX).

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Publié sur : Congrès UICC, Olso - 2002
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Long-term results of comprehensive treatment for non-metastatic primary limb high-grade osteosarcoma. Emphasis of escalating high dose methotrexate (HDMTX).
G. Delepine, H. Cornille, B. Brun, S.Alkallaf, B. Markowska, Nicole Delepine

Long-term results of comprehensive treatment for non-metastatic primary limb high-grade osteosarcoma. Emphasis of escalating high dose methotrexate (HDMTX).



Purpose of this study


Evaluation of effects of escalating induction HDMTX on toxicity, response of tumours and survival of patients with osteosarcoma.

osteosarcoma


Patients


From 1/85 to 12/2000 : 46 patients with non metastatic limb osteosarcoma, previously untreated. 29 M, 17 F (7 - 30 y, mean : 16.6) were treated in one of AP-HP oncologic service.

osteosarcoma


Size of the tumours


osteosarcoma


MTX dose of first course


MTX dose of first course was adapted to age :
- 5-9 y : 18 g/m²,
- 10/15 y : 15 g/m²,
- > 15 : 12 g/sqm.
For the same dose inter patient variability of serum peaks was high.

osteosarcoma


Dose escalation schedule


MTX was escalated from 2 to 4 gr/sqm if the serum peak H6 < 1000 µmol/l
or in case of clinical ineffectiveness.
osteosarcoma


Correlation between H6 and dose


In each patient Correlation between H6 (µmol/l) and dose (gr/sqm) was  linear.

osteosarcoma


Frequency of dose escalation


Escalation was necessary in 80 % of patients (37/46) due to low H6 (13), lack of clinical response (9) or both (15).

osteosarcoma


Preoperative dose escalation


Average increase of dose was 40 % p. received a mean preoperative dose : 14.3 gr/m²/course (8-24 g/m²), mean H6 : 1248 µmol/l (570-3600).

Observed toxicity


Induction therapy was well tolerated.
The most frequent postoperative toxicity was hematologic grade 4 : 90 % of IPA (IFO, CDDP, ADR).

Limiting factor of dose escalation


Hepatic toxicity was the main limiting factor of postoperative MTX.
Observed in 60 courses of MTX (7 %) it resulted in early stopping of MTX in 4 patients.

Radiological responses


osteosarcoma

Good in 30
Stable disease : l2
Inevaluable : 4

Local treatment


All patients were primarly treated by limb salvage even in case of :
Huge tumor
Young child
Fracture.
osteosarcoma


Histological Response


Graded according Huvos and Rosen criteria was :
good : in 25,
bad : 21.

Total doses of MTX therapy


Total doses of MTX therapy given dose of MTX Averaged 250 g/sqm in 41 wks.
Mean MTX intensity 6.3 g/m²/week,
Mean value H6 : 1380 µmol/l.

Oncologic results


Relapses : out of 46 patients, we observed one local and 7 distant relapses, 4 lung, 3 bone.
Average time to relapse was 25 m. (8-75).
Final outcome :
2 p. died, 2 p. are living with evolutive disease
42 others are in CR.
osteosarcoma


Conclusions


In our patients escalating doses following Rosen's rules and pharmacokinetics monitoring permits :
1. The given dose of methotrexate, the dose intensity and the serum concentration X time, to be increased by 40 % in patients who needed it.
2. To increase the event free, the disease free and the overall survival rate of patients.
3. Without severe increase of toxicity.
Protocols for OS should require not only a good total (> 240 g/sqm) dose MTX but a serum peak over 1000 µmol/l at after 6 hours infusion or 1450 µmol/l after 4 hours infusion.



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