Cyclophosphamide dose escalation in combination with vincristine and actinomycin-D (VAC) in gross residual sarcoma: A pilot study without hematopoietic growth factor support evaluating toxicity and response

Frederick B. Ruymann, Teresa Vietti, Edmund Gehan, Eugene Wiener, Moody Wharam, William A. Newton, Harold Maurer

Research output: Contribution to journalArticle

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Abstract

Purpose: The Intergroup Rhabdomyosarcoma Study (IRS) initiated an escalating-dose cyclophosphamide (Cyc) pilot without hematopoietic growth factor (HGF) support in combination with vincristine (Vcr) and actinomycin-D (Amd), known as VAC, to establish a Cyc dose with myelotoxicity comparable to an ifosfamide (Ifos), Vcr, and Amd combination regimen (VAI). A Cyc dose equivalent to Ifos was to be determined when comparable myelotoxicity was achieved. Patients and Methods: Patients with either rhabdomyosarcoma or undifferentiated soft-tissue sarcoma and gross residual (clinical group III) disease were eligible for the VAC pilot. Feasibility and toxicity were evaluated in the VAC pilot at each Cyc level before escalating the dose. Starting at CYC 1.2 g/m2dose escalation was planned at increments of 20–25% in cohorts of 8–10 patients until myelotoxicity at a severe or worse grade was seen in >90% of the patients. Results: One hundred nineteen eligible patients were evaluated for toxicity and response at four Cyc levels: 1.2, 1.5, 1.8, and 2.2 g/m2. Eight of 87 (9%) evaluable at 2.2 g/m2had a toxic death. Six of these were attributable to myelotoxicity. Patients age 1–3 years were most vulnerable. The overall complete response (CR) rate of 68% was poorly predicted by the weeks 8 and 20 CR rates of 20 and 40%, respectively. During the first year and overall, myelotoxicity at 2.2 g/m21 with VAC was comparable to Ifos 1.8 g/m25. Cyc was relatively more myelotoxic than Ifos in the second year of the VAC pilot. Based on actual amount of drug given, a standardized Ifos dose of 9.0 g/m2was equivalent to 2.1 g/m2of Cyc, giving an Ifos/Cyc ratio of 4.3. Conclusion: Myelotoxicity using 2.2 g Cyc/m2in a single intravenous infusion was dose limiting in this VAC pilot without HGF. In the first year and overall, myelotoxicity is comparable to that with VAI using Ifos at 9.0 g/m2. An ongoing IRS-IV randomized trial of VAC and VAI should provide a comparison of the efficacy of Ifos and Cyc in children and adolescents with embryonal or alveolar rhabdomyosarcoma and undifferentiated softtissue sarcomas.

Original languageEnglish (US)
Pages (from-to)331-337
Number of pages7
JournalJournal of Pediatric Hematology/Oncology
Volume17
Issue number4
DOIs
StatePublished - Nov 1995

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Dactinomycin
Vincristine
Ifosfamide
Sarcoma
Cyclophosphamide
Intercellular Signaling Peptides and Proteins
Rhabdomyosarcoma
Alveolar Rhabdomyosarcoma
Embryonal Rhabdomyosarcoma
Poisons
Intravenous Infusions

Keywords

  • Cyclophosphamide
  • Hyperfractionated radiotherapy
  • Ifosfaraide
  • Soft-tissue sarcoma

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Cyclophosphamide dose escalation in combination with vincristine and actinomycin-D (VAC) in gross residual sarcoma : A pilot study without hematopoietic growth factor support evaluating toxicity and response. / Ruymann, Frederick B.; Vietti, Teresa; Gehan, Edmund; Wiener, Eugene; Wharam, Moody; Newton, William A.; Maurer, Harold.

In: Journal of Pediatric Hematology/Oncology, Vol. 17, No. 4, 11.1995, p. 331-337.

Research output: Contribution to journalArticle

Ruymann, Frederick B. ; Vietti, Teresa ; Gehan, Edmund ; Wiener, Eugene ; Wharam, Moody ; Newton, William A. ; Maurer, Harold. / Cyclophosphamide dose escalation in combination with vincristine and actinomycin-D (VAC) in gross residual sarcoma : A pilot study without hematopoietic growth factor support evaluating toxicity and response. In: Journal of Pediatric Hematology/Oncology. 1995 ; Vol. 17, No. 4. pp. 331-337.
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abstract = "Purpose: The Intergroup Rhabdomyosarcoma Study (IRS) initiated an escalating-dose cyclophosphamide (Cyc) pilot without hematopoietic growth factor (HGF) support in combination with vincristine (Vcr) and actinomycin-D (Amd), known as VAC, to establish a Cyc dose with myelotoxicity comparable to an ifosfamide (Ifos), Vcr, and Amd combination regimen (VAI). A Cyc dose equivalent to Ifos was to be determined when comparable myelotoxicity was achieved. Patients and Methods: Patients with either rhabdomyosarcoma or undifferentiated soft-tissue sarcoma and gross residual (clinical group III) disease were eligible for the VAC pilot. Feasibility and toxicity were evaluated in the VAC pilot at each Cyc level before escalating the dose. Starting at CYC 1.2 g/m2dose escalation was planned at increments of 20–25{\%} in cohorts of 8–10 patients until myelotoxicity at a severe or worse grade was seen in >90{\%} of the patients. Results: One hundred nineteen eligible patients were evaluated for toxicity and response at four Cyc levels: 1.2, 1.5, 1.8, and 2.2 g/m2. Eight of 87 (9{\%}) evaluable at 2.2 g/m2had a toxic death. Six of these were attributable to myelotoxicity. Patients age 1–3 years were most vulnerable. The overall complete response (CR) rate of 68{\%} was poorly predicted by the weeks 8 and 20 CR rates of 20 and 40{\%}, respectively. During the first year and overall, myelotoxicity at 2.2 g/m21 with VAC was comparable to Ifos 1.8 g/m25. Cyc was relatively more myelotoxic than Ifos in the second year of the VAC pilot. Based on actual amount of drug given, a standardized Ifos dose of 9.0 g/m2was equivalent to 2.1 g/m2of Cyc, giving an Ifos/Cyc ratio of 4.3. Conclusion: Myelotoxicity using 2.2 g Cyc/m2in a single intravenous infusion was dose limiting in this VAC pilot without HGF. In the first year and overall, myelotoxicity is comparable to that with VAI using Ifos at 9.0 g/m2. An ongoing IRS-IV randomized trial of VAC and VAI should provide a comparison of the efficacy of Ifos and Cyc in children and adolescents with embryonal or alveolar rhabdomyosarcoma and undifferentiated softtissue sarcomas.",
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T2 - A pilot study without hematopoietic growth factor support evaluating toxicity and response

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AU - Vietti, Teresa

AU - Gehan, Edmund

AU - Wiener, Eugene

AU - Wharam, Moody

AU - Newton, William A.

AU - Maurer, Harold

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N2 - Purpose: The Intergroup Rhabdomyosarcoma Study (IRS) initiated an escalating-dose cyclophosphamide (Cyc) pilot without hematopoietic growth factor (HGF) support in combination with vincristine (Vcr) and actinomycin-D (Amd), known as VAC, to establish a Cyc dose with myelotoxicity comparable to an ifosfamide (Ifos), Vcr, and Amd combination regimen (VAI). A Cyc dose equivalent to Ifos was to be determined when comparable myelotoxicity was achieved. Patients and Methods: Patients with either rhabdomyosarcoma or undifferentiated soft-tissue sarcoma and gross residual (clinical group III) disease were eligible for the VAC pilot. Feasibility and toxicity were evaluated in the VAC pilot at each Cyc level before escalating the dose. Starting at CYC 1.2 g/m2dose escalation was planned at increments of 20–25% in cohorts of 8–10 patients until myelotoxicity at a severe or worse grade was seen in >90% of the patients. Results: One hundred nineteen eligible patients were evaluated for toxicity and response at four Cyc levels: 1.2, 1.5, 1.8, and 2.2 g/m2. Eight of 87 (9%) evaluable at 2.2 g/m2had a toxic death. Six of these were attributable to myelotoxicity. Patients age 1–3 years were most vulnerable. The overall complete response (CR) rate of 68% was poorly predicted by the weeks 8 and 20 CR rates of 20 and 40%, respectively. During the first year and overall, myelotoxicity at 2.2 g/m21 with VAC was comparable to Ifos 1.8 g/m25. Cyc was relatively more myelotoxic than Ifos in the second year of the VAC pilot. Based on actual amount of drug given, a standardized Ifos dose of 9.0 g/m2was equivalent to 2.1 g/m2of Cyc, giving an Ifos/Cyc ratio of 4.3. Conclusion: Myelotoxicity using 2.2 g Cyc/m2in a single intravenous infusion was dose limiting in this VAC pilot without HGF. In the first year and overall, myelotoxicity is comparable to that with VAI using Ifos at 9.0 g/m2. An ongoing IRS-IV randomized trial of VAC and VAI should provide a comparison of the efficacy of Ifos and Cyc in children and adolescents with embryonal or alveolar rhabdomyosarcoma and undifferentiated softtissue sarcomas.

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KW - Hyperfractionated radiotherapy

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