Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Patients With Previously Untreated Rhabdomyosarcoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	Under 50	NCI	COG-D9803 CCG-D9803, POG-D9803, IRS-D9803, NCT00003958, D9803

Objectives

1. Compare the early response rates, failure-free survival, and survival of patients with intermediate-risk rhabdomyosarcoma treated with surgery, radiotherapy, and vincristine, dactinomycin, and cyclophosphamide (VAC) vs VAC alternating with vincristine, topotecan, and cyclophosphamide.
2. Compare the acute and late effects of these two treatment regimens in these patients.
3. Determine the rate of second-look surgery in selected patients with bulk residual tumor at diagnosis (i.e., Clinical Group III) and the proportion of these that render the patient tumor free or with microscopic tumor only.
4. Determine the rate of local failure in selected patients with bulk residual tumors at diagnosis (i.e., Clinical Group III) who, after second-look resection, have response-adjusted radiotherapy dose reduction.
5. Determine if preoperative radiotherapy followed by second-look surgery is feasible for selected patients with bulk residual disease (i.e., Clinical Group III) who respond poorly to induction chemotherapy.

Entry Criteria

Disease Characteristics:

• Histologically proven disease of any of the following types:
  • Nonmetastatic alveolar rhabdomyosarcoma
    • Stage I, II, or III; Clinical Group I, II, or III
  • Stage II or III, Clinical Group III embryonal rhabdomyosarcoma
    • Botryoid
    • Spindle cell
  • Under 10 years, stage IV, Clinical Group IV embryonal rhabdomyosarcoma
    • Botryoid
    • Spindle cell
  • Undifferentiated sarcoma
    • Stage I, II, or III; Clinical Group I, II, or III
  • Ectomesenchymoma
    • Stage I, II, or III; Clinical Group I, II, or III, with alveolar features
    • Under 10 years, Stage IV, Clinical Group IV, with embryonal features
• No more than 6 weeks since initial surgical procedure (e.g., biopsy) giving the definitive diagnosis
• No parameningeal rhabdomyosarcoma with positive CSF cytology or multiple intracranial metastases

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior steroids allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• See Disease Characteristics

Patient Characteristics:

Age:

• Under 50

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 1.5 mg/dL

Renal:

• Creatinine normal* for age

 [Note: *Patients with tumor obstruction causing creatinine elevation may be enrolled]

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 518 patients will be accrued for this study within 5 years.

Outcomes

Early response rate (ERR) (i.e., complete response/partial response [CR/PR]) at end of therapy & at 3, 5, and 10 yrs after completion of therapy
Failure-free survival (FFS) at end of therapy & at 3, 5, and 10 yrs after completion of therapy
Survival at end of therapy & at 3, 5, and 10 yrs after completion of therapy
Acute and late effects (e.g., sterility, second malignancy, radiation effects, and growth effects) of these regimens continuously for up to 10 years

Rate of second-look surgery in patients with bulk residual tumor at diagnosis and those who become "tumor free" or have microscopic tumor only and are treated with reduced dose radiation at the end of therapy
Rate of local failure in selected patients with bulk residual tumors at diagnosis who undergo second-look resection and response-adjusted radiotherapy dose reduction ongoing for up to 10 years
Preoperative radiotherapy followed by second-look surgery indicated for patients who respond poorly to induction chemotherapy
Define and compare clinical features (demographics such as age, disease site and stage, node involvement, or outcome) of patient subgroups with alveolar rhabdomyosarcoma whose tumors carry t(2;13), t(1;13) or neither transloc. at end of the study
Estimation of ERR, FFS, and survival of patients with alveolar rhabdomyosarcoma with t(2;13), t(1;13), or neither transloc. by pos. or neg. RTPCR on peripheral blood and marrow spec. at diagnosis and at end of tx

Outline

This is a randomized, multicenter study. Patients are stratified according to disease (embryonal histology, stage II or III, Clinical Group III vs embryonal histology, Clinical Group IV, less than 10 years of age vs alveolar or undifferentiated sarcoma histology, stage I, Clinical Group I vs alveolar or undifferentiated sarcoma histology, stage II or III, Clinical Group II or III). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive vincristine IV over 5-10 minutes once a week on weeks 0-12, 15, 18-24, 27, 30-36, and 39. Dactinomycin IV is administered over 15-20 minutes once a week on weeks 0, 3, 6, 9, 12, 21, 24, 27, 30, 33, 36, and 39. Cyclophosphamide IV is administered over 30-60 minutes once a week on weeks 0, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, and 39. After the initial 12 weeks of chemotherapy, depending on tumor shrinkage, patients may undergo surgery. After recovery from surgery, patients receive radiotherapy once a day, 5 days a week, during weeks 12-18. For patients receiving radiotherapy during weeks 0-6, dactinomycin is omitted during weeks 3 and 6 and administered during weeks 15 and 18. For patients receiving radiotherapy during weeks 12-18, dactinomycin is omitted during weeks 15 and 18. Patients showing an adequate response at week 24 continue chemotherapy during weeks 24-39.

  Patients with Clinical Group III tumors of a parameningeal site with documented evidence of intracranial extension receive radiotherapy within the first 2 weeks of the initiation of the first course of chemotherapy (day 0).

  Patients with Clinical Group II parameningeal tumors and Clinical Group III parameningeal tumors with base of skull erosion and/or cranial nerve palsy without evidence of intracranial extension receive radiotherapy on week 12 (day 84) or immediately thereafter.

  Patients with Clinical Group IV parameningeal tumors with distant metastases receive radiotherapy to the primary site on week 12 (day 84). Patients with distant metastases confined to one site may receive radiotherapy to the metastatic site concurrently with therapy to the primary site if it began within 2 weeks of the initiation of chemotherapy (day 0).

• Arm II: Patients receive treatment as in arm I, except dactinomycin is replaced with topotecan IV over 15-30 minutes daily for 5 days during weeks 3, 9, 21, 27, 33, and 39.

All patients receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously beginning 24 hours after completion of each course of chemotherapy and continuing 1 year, until hematopoietic recovery.

Patients are followed every 1-2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Arndt CA, Stoner JA, Hawkins DS, et al.: Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol 27 (31): 5182-8, 2009.[PUBMED Abstract]

Arndt CA, Hawkins DS, Stoner JA, et al.: Randomized phase III trial comparing vincristine, actinomycin, cyclophosphamide (VAC) with VAC/V topotecan/cyclophosphamide (TC) for intermediate risk rhabdomyosarcoma (IRRMS). D9803, COG study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9509, 528s, 2007.

Arndt C, Hawkins D, Anderson JR, et al.: Age is a risk factor for chemotherapy-induced hepatopathy with vincristine, dactinomycin, and cyclophosphamide. J Clin Oncol 22 (10): 1894-901, 2004.[PUBMED Abstract]

Petricoin EF 3rd, Espina V, Araujo RP, et al.: Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res 67 (7): 3431-40, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Carola Arndt, MD, Protocol chair		Ph: 507-284-3442 Email: carndt@mayo.edu

Registry Information
Official Title		Randomized Study of Vincristine, Actinomycin-D, and Cyclophosphamide (VAC) versus VAC Alternating with Vincristine, Topotecan and Cyclophosphamide for Patients with Intermediate-Risk Rhabdomyosarcoma
Trial Start Date		2002-09-01
Registered in ClinicalTrials.gov		NCT00003958
Date Submitted to PDQ		1999-06-25
Information Last Verified		2005-01-10
NCI Grant/Contract Number		CA24507

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