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

Cindy L. Schwartz, Leonard H. Wexler, Mark D. Krailo, Lisa A. Teot, Meenakshi Devidas, Laurel J. Steinherz, Allen M. Goorin, Mark C. Gebhardt, John H. Healey, Judith K. Sato, Paul A. Meyers, Holcombe E. Grier, Mark L. Bernstein, Steven E Lipshultz

Research output: Contribution to journalArticle

33 Citations (Scopus)

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/m2) 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/m2) 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.

Original languageEnglish (US)
Pages (from-to)54-61
Number of pages8
JournalPediatric Blood and Cancer
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Dexrazoxane
Osteosarcoma
Doxorubicin
Drug Therapy
Ifosfamide
Induction Chemotherapy
Necrosis
Etoposide
Neoplasms
Anthracyclines
Left Ventricular Dysfunction
Methotrexate
Cisplatin
Survivors
Leukemia
Morbidity
Mortality

Keywords

  • Dexrazoxane cardioprotection
  • Intensified chemotherapy
  • Newly diagnosed
  • Nonmetastatic osteosarcoma

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Medicine(all)
  • Hematology
  • Oncology

Cite this

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma : A Report From the Children's Oncology Group. / Schwartz, Cindy L.; Wexler, Leonard H.; Krailo, Mark D.; Teot, Lisa A.; Devidas, Meenakshi; Steinherz, Laurel J.; Goorin, Allen M.; Gebhardt, Mark C.; Healey, John H.; Sato, Judith K.; Meyers, Paul A.; Grier, Holcombe E.; Bernstein, Mark L.; Lipshultz, Steven E.

In: Pediatric Blood and Cancer, Vol. 63, No. 1, 01.01.2016, p. 54-61.

Research output: Contribution to journalArticle

Schwartz, CL, Wexler, LH, Krailo, MD, Teot, LA, Devidas, M, Steinherz, LJ, Goorin, AM, Gebhardt, MC, Healey, JH, Sato, JK, Meyers, PA, Grier, HE, Bernstein, ML & Lipshultz, SE 2016, 'Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group', Pediatric Blood and Cancer, vol. 63, no. 1, pp. 54-61. https://doi.org/10.1002/pbc.25753
Schwartz, Cindy L. ; Wexler, Leonard H. ; Krailo, Mark D. ; Teot, Lisa A. ; Devidas, Meenakshi ; Steinherz, Laurel J. ; Goorin, Allen M. ; Gebhardt, Mark C. ; Healey, John H. ; Sato, Judith K. ; Meyers, Paul A. ; Grier, Holcombe E. ; Bernstein, Mark L. ; Lipshultz, Steven E. / Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma : A Report From the Children's Oncology Group. In: Pediatric Blood and Cancer. 2016 ; Vol. 63, No. 1. pp. 54-61.
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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/m2) 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/m2) 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.",
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T1 - Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma

T2 - 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

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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/m2) 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/m2) 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.

AB - 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/m2) 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/m2) 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.

KW - Dexrazoxane cardioprotection

KW - Intensified chemotherapy

KW - Newly diagnosed

KW - Nonmetastatic osteosarcoma

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