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

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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).

Purpose of this study

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

Size of the tumours

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.

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.

Correlation between H6 and dose

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

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).

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

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.

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.

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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