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Non-metastatic Osteosarcoma: Response based augmentatation of therapy . P9754 A Children’s Oncology Group Study Schwartz CL, Wexler LH, Devidas M, Teot LA, Goorin A, Grier H, Gebhard M, Steinherz L, Sato J, Healey J, Lipshultz S, Miser J, Womer R, Meyers P, Bernstein M. P9754 BACKGROUND.

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Non-metastatic Osteosarcoma: Response based augmentatation of therapy

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Non metastatic osteosarcoma response based augmentatation of therapy l.jpg

Non-metastatic Osteosarcoma: Response based augmentatation of therapy

P9754

A Children’s Oncology Group Study

Schwartz CL, Wexler LH, Devidas M, Teot LA, Goorin A, Grier H, Gebhard M, Steinherz L, Sato J, Healey J, Lipshultz S, Miser J, Womer R, Meyers P, Bernstein M


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P9754 BACKGROUND

  • Percent necrosis (% NEC) is predictive of EFS

  • Dose Intensity is associated with outcome

  • Acute & long term cardiac toxicity significant

  • Understanding biology will allow prognosis


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P9754:OBJECTIVES

Although chemotherapy has improved outcome for OS, patients continue to experience recurrence and death. P9754 was designed to:

  • Evaluate the safety of augmenting chemotherapy with doxorubicin (600mg/m2 cumulative dose) or ifosfamide (14 g/m2/cycle).

  • Determine if dexrzoxane (DXR) cardioprotection during pre-operative induction chemotherapy affects histologic response.

  • Assess feasiblity of collecting tumor tissue for biologic investigation.


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P9754: Sequential Pilot Studies to Augment Therapy

  • #1: Doxo intensification to 600mg/m2

    with dexrazoxane

  • #2: Doxo intensification to 600mg/m2

    with dexrazoxane and ifosfamide

  • #3: Ifosfamide/Etoposide intensification


Therapy p9754 l.jpg

CDDP: 120 mg/m2/cycle X4

MTX = 12 g/m2 X 12,

Doxo 75 mg/m2 x 6

Therapy: P9754

Induction

10 weeks

Surgery

Post-op Chemotx

GR

Continue 3 drugs

For 22 weeks

Pilot 1

MTX, CDDP, Doxo

Doxo

Intensification

3 drugs with

Doxo to 600 mg/m2 cum.

SR

Pilot 2

MTX, CDDP, Doxo

Ifos (9g/m2)

4 drugs with

Doxo to 600 mg/m2 cm.

Continue 4 drugs

for 22 weeks

GR

Pilot 3

MTX, CDDP, Doxo,

Ifos

Ifos/Etoposide Intensification

SR

4 drugs with

VP16/Ifos (14g/m2 /cycle)


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Results: Sequential Pilots

  • Original projection: 60 patients/pilot, 90 SR

  • 253 enrolled, 242 eligible, 221 evaluate response

    • Surgical delay  not evaluable

      Additional accrual to pilot 1 (DOXO @600 mg/m2)

      Pilot 1: 112 Pilot 2: 54 Pilot 3: 55

Pilot 1

9/1999 – 6/2000

Pilot 3

6/00- 1/00

Pilot 2

11/00 - 5/01

Pilot 1

5/01 – 10/01


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Results: Toxicity

At 30 months:

mean FS 33.8 vs. 34.6 for 450 vs. 600 doxo treatment arms

(based on very limited numbers entered on LE RDE form)


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Response to Preoperative Chemotherapy: Percent Necrosis

Historic Control (POG8651): 30% had > 98% Necrosis

* Of those evaluable for response

No adverse effect on % Necrosis with dexrazoxane


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Event Free Survival for Good & Standard Response

EFS at 4 yrs

GR: 79.1 + 6.2%

SR: 55.2 + 5.3%

Pilot 1: EFS @ 4 yrs

GR: 73.8 + 10.9%

SR: 51.8 + 8.2%

Pilot 2: EFS @ 4 yrs

GR: 76.2 + 9.3%

SR: 57.1 + 9.1%

Pilot 3: EFS @ 4 yrs

GR: 88.9 + 8.2%

SR: 60.7 + 8.5%


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EFS by Pilot

EFS at 4 yr

Pilot

1: 55.0 + 6.5%

2: 65.9 +8.6%

3: 70.0 + 6.5%


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P9754 Overall Survival by pilot

OS at 4 yr

Pilot

1: 69.7 + 5.9%

2: 78.9 + 7.0%

3: 76.3 + 6.0%


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Biologic Specimens

  • POG 9851: Biology Trial

  • Specimens submitted on 213 of 253 enrolled on P9754


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Conclusions

  • Dose intensification

    • Feasible with high cumulative dose doxorubicin OR etoposide/high dose ifosfamide

    • EFS Difference of SR vs. GR. remains statistically significant

    • EFS/OS is similar to prior studies (eg. INT 0133)

    • No statistically significant difference between pilots at this time.

      Randomized studies needed to determine benefit of IE augmentation

  • Cardioprotection by Dexrazoxane

    • ~ 2% acute cardiotoxicity WITH DEXRAZOXANE: including patients receiving DOXO up to 600 mg/m2

    • % NEC not reduced by Dexrazoxane vs. historical controls.

      Further studies should address the role of DXR in reducing long term anthracycline induced cardiotoxicity

  • Biology

    • Tumor banking was feasible: 84% submission rate


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