Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group

Abstract

Background: Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.

Procedure: Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery).

Results: Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible.

Conclusions: Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.

Keywords: dexrazoxane cardioprotection; intensified chemotherapy; newly diagnosed; nonmetastatic osteosarcoma.

Figure 1

The chemotherapy used includes ifosfamide (i): 1.8 g/m²/d × 5 days with MESNA (360 mg/m²/dose 5 daily for 5 days, high dose ifosfamide (I): 2.8 g/m²/d × 5 = 14 g/m² with MESNA (560 mg/m²/dose) 5 daily for 5 days, cisplatin (P): 60 mg/m²/d × 2 days, methotrexate (M): 12 g/m² with leucovorin 15 mg every 6 hours, doxorubicin (a): 37.5 mg/m²/d × 2 days with dexrazoxane 375 mg/m² before each dose, and etoposide (e) as 100 mg/m²/d × 5 days.

Figure 2

Change in left ventricular fractional shortening, with time up to week 78, is shown for all patients with the same rate of delivery of doxorubicin (excluding etoposide/ifosfamide intensification). Blue squares represent all FCZ values for patients who received a total dose up 450 mg/m² and FCZ values obtained prior to the time of augmented doxorubin doses in SR on pilots 1 and 2. Red astericks represent FCZ obtained after the time when more tan 450 mg/m2 would have been administered to SR on pilots 1 and 2.

Figure 3

EFS and OS for P9754 are shown in 3A where the blue line represents EFS and the red dashed line represents OS. Figure 3B shows EFS by pilot since maintenance (p= 0.40). The blue line represents Pilot 1, the red dashed line represents Pilot 2, and the green dashed and dotted lines represent pilot 3. Figure 3C shows the EFS of SR patients by pilot since maintenance (p= 0.560). The blue line represents Pilot 1, the red dashed line represents Pilot 2, and the green dashed and dotted lines represent pilot 3. Figure 3D shows Overall Survival by pilot since maintenance (p=0.38). The blue line represents Pilot 1, the red dashed line represents Pilot 2, and the green dashed and dotted lines represent pilot 3. Figure 3E shows Overall survival of SR patients by pilot since maintenance (p=0.69) The blue line represents Pilot 1, the red dashed line representa Pilot 2, and the green dashed and dotted lines represent pilot 3. Figure 3F shows EFS since maintenance for Good vs. Standard Responders (p=0.001). The blue line represents good response and the red dashed line represents standard response. Figure 3G shows OS since maintenance for Good vs. Standard Responders (p=0.002) The blue line representing good response and the red dashed line representing standard response