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Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group.
Pediatr Blood Cancer 2016; 63(1):54-61PB

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.

Authors+Show Affiliations

MD Anderson Cancer Center, Houston, Texas.Memorial Sloan Kettering Cancer Center, New York, New York.University of Southern California, Los Angeles, California.Dana-Farber Cancer Institute, Boston, Massachusetts.University of Florida College of Medicine and Children's Oncology Group, Gainesville, Florida.Memorial Sloan Kettering Cancer Center, New York, New York.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Memorial Sloan Kettering Cancer Center, New York, New York.City of Hope National Medical Center, Pasadena, California.Memorial Sloan Kettering Cancer Center, New York, New York.Dana-Farber Cancer Institute, Boston, Massachusetts.IWK Health Centre, Nova Scotia, Canada.Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, Michigan.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26398490

Citation

Schwartz, Cindy L., et al. "Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: a Report From the Children's Oncology Group." Pediatric Blood & Cancer, vol. 63, no. 1, 2016, pp. 54-61.
Schwartz CL, Wexler LH, Krailo MD, et al. Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group. Pediatr Blood Cancer. 2016;63(1):54-61.
Schwartz, C. L., Wexler, L. H., Krailo, M. D., Teot, L. A., Devidas, M., Steinherz, L. J., ... Lipshultz, S. E. (2016). Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group. Pediatric Blood & Cancer, 63(1), pp. 54-61. doi:10.1002/pbc.25753.
Schwartz CL, et al. Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: a Report From the Children's Oncology Group. Pediatr Blood Cancer. 2016;63(1):54-61. PubMed PMID: 26398490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group. AU - Schwartz,Cindy L, AU - Wexler,Leonard H, AU - Krailo,Mark D, AU - Teot,Lisa A, AU - Devidas,Meenakshi, AU - Steinherz,Laurel J, AU - Goorin,Allen M, AU - Gebhardt,Mark C, AU - Healey,John H, AU - Sato,Judith K, AU - Meyers,Paul A, AU - Grier,Holcombe E, AU - Bernstein,Mark L, AU - Lipshultz,Steven E, Y1 - 2015/09/23/ PY - 2015/02/23/received PY - 2015/07/28/accepted PY - 2015/9/24/entrez PY - 2015/9/24/pubmed PY - 2016/4/26/medline KW - dexrazoxane cardioprotection KW - intensified chemotherapy KW - newly diagnosed KW - nonmetastatic osteosarcoma SP - 54 EP - 61 JF - Pediatric blood & cancer JO - Pediatr Blood Cancer VL - 63 IS - 1 N2 - 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. SN - 1545-5017 UR - https://www.unboundmedicine.com/medline/citation/26398490/Intensified_Chemotherapy_With_Dexrazoxane_Cardioprotection_in_Newly_Diagnosed_Nonmetastatic_Osteosarcoma:_A_Report_From_the_Children's_Oncology_Group_ L2 - https://doi.org/10.1002/pbc.25753 DB - PRIME DP - Unbound Medicine ER -