Publié sur : Power point Nicole Delépine - International Society of Limb Salvage - 2003
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Long term follow up of osteosarcoma treated with multidisciplinary treatment
G. Delepine, F. Delepine, Nicole Delepine

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Long term follow up of osteosarcoma treated with multidisciplinary treatment

Purpose of this study

Evaluation of effects of protocols :
Bidrug therapy Doxo+CCDP) versus HDMTX and for MTX evaluation of escalating induction on toxicity, response of tumours and survival of patients with osteosarcoma.

Patients (1980 to 1995)

106 patients with primary high grade OS fulfilled the classical criteria : non metastatic, resectable tumor, previously untreated, definitive local treatment administered by the team after preoperative chemotherapy.

65 men and 41 women (4 to 45 years ; median. : 16.8.) 12 p. had upper limb lesions (10 humerus and 2 scapula), 93 lower limb locations (54 femoral, 34 tibial, 2 fibula and 2 inonimate bones, one foot) and 1 maxillar.

Size of the tumors

The average diameter of tumor was 12 centimeters (5-28).

Treatment

- Group 1 : 16 p. received 6 Doxo-CDDP (total dose 300 mg/m² Doxo and 600 mg/m² of CDDP) for 20 weeks.
- Group 2 : 45 p. received a fixed dose of MTX adapted only to age. 35 received part of CT in other centers.

Group 3 (OS DD Protocols)

45 p. received escalating doses of MTX.
The dose of the first course was adapted to age.
The doses of subsequent courses were adapted to the seric PK of each p.
and to the response of the tumor in order to reach a serum peak of 1000 µmol/l at the end of the 6 hours infusion and to achieve an objective response.

(OS DD) MTX dose of first course

The dose of the 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.

(OS DD) Dose escalation schedule

The doses of subsequent courses were adapted to the seric PK of each p. And to the response of the tumor in order to reach a serum peak of 1000 µmol/l at the end of the 6 hours infusion and to achieve an objective response.

Local treatment

1 had a radical hip desarticulation others underwent limb salvage.
In 18 bad responders marginal resection received local radiotherapy.

Results

G2 p. received a mean dose of 10,5 g/m²/course and G3 p. a mean dose of 13.5 g/m²/course (mean seric concentration of respectively 850 µmol/l and 1175 µmol/l).
In G3 a dose escalation was necessary in nearly 70 % of cases (32/45) due to low serum concentration (15), lack of clinical response (9) or both (8). The average dose increase was 35 % of the first given dose.

Limiting factor of dose escalation

No significant difference in toxicity of MTX was observed in the p. with escalating dose compared to the p. with a fixed dose.
Hepatic toxicity was the main limiting factor of postoperative MTX.
Observed in 7 %) courses of MTX (it resulted in early stopping of MTX in 4 patients.

Local control

6 local recurrences were observed
4 in G2 and 2 in G3.
All 6 p. had a low seric intensity of MTX (early stopping of MTX with drug intensity < 50 % of the planned dose).

Dose escalation of MTX in group 3

A dose escalation was necessary in nearly 70 % of cases (32/45) due to low serum concentration (15), lack of clinical response (9) or both (8).
The average dose increase was 35 % of the first given dose. The mean dose of of MTX of 13.5 g/m²/course (mean seric concentration of 1175 µmol/l).
No significant difference in toxicity was observed in the p. with escalating dose compared to the p. with a fixed dose.

Disease free survival

At a median F.U. of 13.5 years we observed 38 relapses :
- Lungs 27
- Bone 5
- Local and metastatic 4,
- Local recurrence 2.
- Subsequently 29 p. died,
- 77 p. are still alive, 2 with ED, 6 in 2nd CR and 69 are EFS.

Results according to protocols

Conclusion 1 : Bidrug CT with Doxo + Cddp is not effective enough !

Protocols with dose escalation of MTX give best long term results

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