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 1) support escalation of the cumulative doxorubicin dose (600 mg/m2) and 2) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.9 Procedure Children and adolescents with non-metastatic 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/m2) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in 5 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.

Risk–Benefit of Dexrazoxane for Preventing Anthracycline-Related Cardiotoxicity: Re-Evaluating the European Labeling

“…‡ Results from the P9754 trial were also included in the abstract. The results from this trial were published subsequently in reference [14]. § In study 95-01 patients were randomly assigned to receive or not receive DRZ and in study 00-01 all high-risk patients received DRZ.…”

“…Part of the Pediatric Oncology Group/Children's Cancer Group Pilot Intergroup protocol COG P9754 investigated dexrazoxane in 242 patients with osteosarcoma treated with a cumulative doxorubicin dose of 600 mg/m 2 (Table 1) [14]. A third of the patients were over the age of 15 years (up to 30 years old).…”

“…When we limited the results to publications consistent with the revised label for Cardioxane, 13 clinical trials [6][7][8][9][10][11][12][13][14][15][16][17][18] and four meta-analyses or systematic reviews remained [19][20][21][22]. These meta-analyses and systematic…”

“…Dexrazoxane is an effective cardioprotectant in children Since the CHMP review, 11 relevant publications have examined the use of dexrazoxane in children [6,7,[9][10][11][12][14][15][16][17][18]. The Children's Oncology Group (COG) P9404 randomized trial evaluated oncologic efficacy, cardioprotective effectiveness and safety following dexrazoxane therapy in 537 children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic non-Hodgkin lymphoma (Table 1) [6].…”

Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice

“…Because of reports of lower tumor responsiveness or enhanced myelosuppression in chemotherapy-receiving patients treated with dexrazoxane, the US Food and Drug Administration and the European Medicines Agency restricted the use of dexrazoxane (38,47). Although a growing body of literature suggests that dexrazoxane does not adversely affect therapeutic response (28,40,41,53), additional mechanism-based therapies for doxorubicin-induced cardiotoxicity are needed.…”