Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Objectives

I.  Compare, in a Phase III setting, progression-free survival, overall 
survival, and response rates of patients with Stage 4 rhabdomyosarcoma and 
undifferentiated sarcoma randomly assigned to treatment with one of 3 drug 
pairs administered both upfront alone and together with 
vincristine/dactinomycin/cyclophosphamide (VAC) as part of maintenance therapy 
in responders:  vincristine/melphalan (VM) vs. ifosfamide/etoposide (IE) vs. 
ifosfamide/doxorubicin (ID).  (Data from the pilot IRS IV study will be used 
for the ID regimen, and patients on this protocol will be randomized to VM and 
IE only).

II.  Determine whether there is clinical cross-resistance between the drug 
pairs used upfront and VAC maintenance chemotherapy in patients who achieve 
less than CR on the 2-drug induction therapy.

III.  Investigate the relationship between immunohistochemical patterns of 
tumor and prognosis, and evaluate newly identified immunohistochemical markers 
in diagnosis.

IV.  Correlate clinical features of disease and prognosis with tumor 
cytogenetics, DNA labeling index, and amplification or rearrangement of 
specific cellular proto-oncogenes.

V.  Provide a bank of frozen tumor tissue for use in tumor biology studies.

VI.  Evaluate recombinant granulocyte colony stimulating factor as a 
supportive measure for amelioration of hematopoietic toxicity.

Entry Criteria

Disease Characteristics:

  Pathologically documented Stage 4 and/or Clinical Group IV rhabdomyosarcoma
  or undifferentiated sarcoma, type indeterminate

  Patients with Stage 2 or 3 disease found at initial definitive surgery to
  have metastases (Group IV) are eligible for this protocol

  Primary brain and spinal cord rhabdomyosarcoma are excluded

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  Prior steroid therapy allowed

Radiotherapy:
  No prior radiotherapy

Surgery:
  Treatment must begin within 42 days of the surgical procedure (e.g., biopsy)
  that produced the definitive diagnosis

Patient Characteristics:

Age:
  Under 21 at diagnosis

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Creatinine normal for age preferred (patients with elevated creatinine are
  nonrandomly assigned to Arm I)

Other:
  Patients who qualify are registered on companion protocol
  CCG-B904/POG-9153/NCI-INT-0120 (tumor biology protocol)

Expected Enrollment

About 4.7 years will be required in order to enter the required 48 patients on 
each arm.

Outline

Randomized study.  Patients will have undergone excision of as much gross 
tumor as possible prior to initiation of treatment.  Patients with elevated 
serum creatinine are nonrandomly assigned to Arm I, while all others are 
randomized to Arms I and II.  All patients receive radiotherapy (Regimen A) 
during Induction.  Patients who do not respond to 6 weeks of Induction receive 
continuation chemotherapy on Regimen B after completing Induction.  Patients 
with cranial parameningeal primaries and cytologically positive CSF receive 
Triple Intrathecal Therapy (TIT) on Regimen C beginning at the start of 
Induction.

Arm I (Regimen 48):

Induction Phase 1:  2-Drug Combination Chemotherapy with Hematopoietic 
Stimulation.  VM:  Vincristine, VCR, NSC-67574; Melphalan, L-PAM, NSC-8806, 
with Granulocyte Colony Stimulating Factor (Amgen) G-CSF, NSC-614629.

Induction Phase 2:  3-Drug Combination Chemotherapy with Urothelial Protection 
and Hematopoietic Stimulation.  VAC:  VCR; Dactinomycin, DACT, NSC-3053; 
Cyclophosphamide, CTX, NSC-26271; with Mesna, NSC-113891; and G-CSF.

Induction Phase 3 (most patients receive radiotherapy on Regimen A during this 
phase):  2-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VCR; CTX; with Mesna; and G-CSF.

Continuation:  2-Drug Combination Chemotherapy Alternating with and Followed 
by 3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VM; alternating with and followed by VAC; with 
Mesna; and G-CSF.

Arm II (Regimen 49):

Induction Phase 1:  2-Drug Combination Chemotherapy with Urothelial Protection 
and Hematopoietic Stimulation.  IE:  Ifosfamide, IFF, NSC-109724; Etoposide, 
VP-16, NSC-141540; with Mesna; and G-CSF.

Induction Phase 2:  3-Drug Combination Chemotherapy with Urothelial Protection 
and Hematopoietic Stimulation.  VAC; with Mesna; and G-CSF.

Induction Phase 3 (most patients receive radiotherapy on Regimen A during this 
phase):  2-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VCR; CTX; with Mesna; and G-CSF.

Continuation:  3-Drug Combination Chemotherapy with Urothelial Protection 
Alternating with and Followed by 3-Drug Combination Chemotherapy with 
Urothelial Protection and Hematopoietic Stimulation.  VIE:  VCR; IFF; VP-16; 
with Mesna; alternating with and followed by VAC; with Mesna; and G-CSF.

Regimen A:  Radiotherapy.  Involved-field irradiation using Co60 equipment or 
linear accelerators with minimum beam energies of 4-20 MV (electrons and 
brachytherapy may be appropriate in certain situations).

Regimen B (Continuation Regimen G):  3-Drug Combination Chemotherapy with 
Urothelial Protection.  VAC; with Mesna.

Regimen C:  3-Drug Combination Intrathecal Chemotherapy with Leucovorin 
Rescue.  Intrathecal Methotrexate, IT MTX, NSC-740; Intrathecal 
Hydrocortisone, IT HC, NSC-10483; Intrathecal Cytarabine, IT ARA-C; with 
Leucovorin calcium, CF, NSC-3590.

Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011.[PUBMED Abstract]

Raney B, Stoner J, Anderson J, et al.: Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group. J Pediatr Surg 45 (11): 2160-8, 2010.[PUBMED Abstract]

Crist W, Anderson J, Maurer H, et al.: Preliminary results for patients with local/regional tumors treated on the Intergroup Rhabdomyosarcoma Study-IV (1991-1997). [Abstract] Proceedings of the American Society of Clinical Oncology 18: 2141A, 555a, 1999.

Pappo AS, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17 (11): 3487-93, 1999.[PUBMED Abstract]

Ortega JA, Donaldson S, Ivy SP, et al.: Venocclusive disease (VOD) of the liver following vincristine-actinomycin D-cyclophosphamide (VAC) therapy for rhabdomyosarcoma (RMS): a report from the Intergroup Rhabdomyosarcoma Study (IRS) group. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-1401, 440, 1995.

Pressey JG, Anderson JR, Crossman DK, et al.: Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 57 (6): 930-8, 2011.[PUBMED Abstract]

Davicioni E, Anderson JR, Buckley JD, et al.: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 28 (7): 1240-6, 2010.[PUBMED Abstract]

Huh WW, Anderson JR, Rodeberg D, et al.: Orbital sarcoma with metastases at diagnosis: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 54 (7): 1045-7, 2010.[PUBMED Abstract]

Hayes-Jordan A, Stoner JA, Anderson JR, et al.: The impact of surgical excision in chest wall rhabdomyosarcoma: a report from the Children's Oncology Group. J Pediatr Surg 43 (5): 831-6, 2008.[PUBMED Abstract]

Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008.[PUBMED Abstract]

Raney RB, Chintagumpala M, Anderson J, et al.: Results of treatment of patients with superficial facial rhabdomyosarcomas on protocols of the Intergroup Rhabdomyosarcoma Study Group (IRSG), 1984-1997. Pediatr Blood Cancer 50 (5): 958-64, 2008.[PUBMED Abstract]

Raney RB, Meza J, Anderson JR, et al.: Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997. Med Pediatr Oncol 38 (1): 22-32, 2002.[PUBMED Abstract]

Walterhouse D, Pappo A, Baker S, et al.: Rhabdomyosarcoma of the parotid region: a report of the Intergroup Rhabdomyosarcoma Study (IRS) Group, studies I to IV. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A2340, 2000.

Kodet R, Newton WA Jr, Hamoudi AB, et al.: Orbital rhabdomyosarcomas and related tumors in childhood: relationship of morphology to prognosis--an Intergroup Rhabdomyosarcoma study. Med Pediatr Oncol 29 (1): 51-60, 1997.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Soft Tissue Sarcoma Committee

Harold Maurer, MD, Protocol chair		Ph: 402-559-4200

Children's Cancer Group

Jorge Ortega, MD, Protocol chair		Ph: 213-669-2163 Email: jortega@chlais.usc.edu

Pediatric Oncology Group

Harold Maurer, MD, Protocol chair		Ph: 402-559-4200

Back to Top