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 of patients 
with stage 2/3 rhabdomyosarcoma and undifferentiated sarcoma randomly assigned 
to treatment with vincristine/dactinomycin/cyclophosphamide (VAC) vs. 
vincristine/dactinomycin/ifosfamide (VAI) vs. vincristine/ifosfamide/etoposide 
(VIE).

II.  Compare hyperfractionated irradiation vs. conventional radiotherapy with 
regard to local relapse rates and acute and late toxicity.

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 rhabdomyosarcoma or undifferentiated
sarcoma, type indeterminate
 Stage 2 or 3 disease eligible if have intermediate risk features
  Not Stage 2, Group I (eligible for IRSG protocol D9602)
  No metastatic disease (i.e., Group IV)

Primary brain and spinal cord rhabdomyosarcoma 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

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

Expected Enrollment

It is estimated that 31 patients with Stage 2 disease and 67 patients with 
Stage 3 disease will be entered per year and that 4.7 years of accrual will be 
necessary.

Outline

Randomized study.  Patients will have undergone excision of as much gross 
tumor as possible prior to entry.  All patients are randomized on Arms I, II, 
and III for chemotherapy.  Clinical Group III patients are randomized for 
hyperfractionated vs. conventional radiotherapy on Arms IV and V; all Clinical 
Group II patients and Clinical Group I Stage 3 patients are nonrandomly 
assigned to Arm V for conventional radiotherapy; Clinical Group I Stage 2 
patients do not receive radiotherapy.

Arm I:  3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VAC (Regimens 40 and 45):  Vincristine, VCR, 
NSC-67574; Dactinomycin, DACT, NSC-3053; Cyclophosphamide, CTX, NSC-26271; 
with Mesna, NSC-113891; and Granulocyte Colony-Stimulating Factor (Amgen), 
G-CSF, NSC-614629.

Arm II:  3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VAI (Regimen 46):  VCR; DACT; Ifosfamide, IFF, 
NSC-109724; with Mesna; and G-CSF.  (VAC replaces VAI for the last 2 
continuation courses.)

Arm III:  3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematopoietic Stimulation.  VIE (Regimen 47):  VCR; IFF; Etoposide, VP-16, 
NSC-141540; with Mesna; and G-CSF.  (VAC replaces VIE for the last 2 
continuation courses.)

Arm IV:  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).  Hyperfractionated 
schedule.

Arm V:  Radiotherapy.  Involved-field irradiation as in Arm IV.  Conventional 
schedule.

Gupta AA, Anderson JR, Pappo AS, et al.: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118 (4): 1130-7, 2012.[PUBMED Abstract]

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]

Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 27 (22): 3705-11, 2009.[PUBMED Abstract]

Arndt C, Rodeberg D, Breitfeld PP, et al.: Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from intergroup rhabdomyosarcoma study iv. J Urol 171 (6 Pt 1): 2396-403, 2004.[PUBMED Abstract]

Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001.[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.

Raney B, Huh W, Hawkins D, et al.: Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (3): 371-6, 2013.[PUBMED Abstract]

La TH, Wolden SL, Rodeberg DA, et al.: Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (4): 1151-7, 2011.[PUBMED Abstract]

La TH, Wolden SL, Su Z, et al.: Local therapy for rhabdomyosarcoma of the hands and feet: is amputation necessary? A report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (1): 206-12, 2011.[PUBMED Abstract]

Malempati S, Rodeberg DA, Donaldson SS, et al.: Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer 117 (15): 3493-501, 2011.[PUBMED Abstract]

Million L, Anderson J, Breneman J, et al.: Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (2): 333-8, 2011.[PUBMED Abstract]

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]

Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 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]

Minn AY, Lyden ER, Anderson JR, et al.: Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS-IV and D9803--a report from the Children's Oncology Group. J Clin Oncol 28 (27): 4228-32, 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

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