High-Dose Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Metastatic Rhabdomyosarcoma or Ectomesenchymoma

OBJECTIVES:

Primary

- Improve the early disease control interval for patients with newly diagnosed, high-risk,
metastatic rhabdomyosarcoma or ectomesenchymoma using intensive, interval-compression
therapy (comprising vincristine, irinotecan hydrochloride, ifosfamide, etoposide,
doxorubicin hydrochloride, cyclophosphamide, and dactinomycin) that permits maximal
early exposure to known effective agents.

- Determine the feasibility of concurrent irinotecan hydrochloride and radiotherapy in
these patients.

- Assess immediate- and short-term side effects of concurrent irinotecan hydrochloride and
radiotherapy in these patients.

Secondary

- Expand the available data for response to irinotecan hydrochloride and vincristine in
previously untreated patients with high-risk rhabdomyosarcoma.

- Evaluate, prospectively, and validate gene expression values with the intent to define
the best diagnostic predictors and more powerful prognostic classifiers.

OUTLINE: This is a prospective, nonrandomized, multicenter study. Patients are stratified
according to prognostic factors predictive of outcome (e.g. histology, bone/bone marrow
involvement, and number of metastatic sites).

Patients receive high-dose chemotherapy comprising vincristine IV over 1 minute on day 1 of
weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51;
irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; and
ifosfamide IV over 1 hour and etoposide IV over 30-60 minutes on days 1-5 of weeks 9, 13, 17,
26, and 30. Patients also receive doxorubicin hydrochloride IV continuously over 24 hours on
days 1 and 2 of weeks 7*, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1
of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; and dactinomycin IV over 1-5 minutes on day 1
of weeks 35, 38, 41, and 44 in the absence of disease progression or unacceptable toxicity.
Patients also receive filgrastim (G-CSF) subcutaneously in weeks 7-9, 11-13, 15-17, 22, 26,
28-30, 32, 33, 35, 38, and 41-44 beginning 24-36 hours after the last chemotherapy dose and
continuing until blood counts recover.

NOTE: *Patients undergoing early radiotherapy for intracranial extension do not receive
doxorubicin in week 7.

Beginning at week 20 (or week 1 for patients with parameningeal tumors with intracranial
extension [or spinal cord compression] requiring emergency radiotherapy), patients also
undergo radiotherapy once a day, 5 days a week, for approximately 5½ weeks. Some patients may
also undergo second-look surgery.

After completion of study treatment, patients are followed periodically for ≥ 10 years.

PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed high-risk rhabdomyosarcoma or ectomesenchymoma

- Prior enrollment on COG-D9902 to confirm local histological diagnosis required

- Tissue must be submitted for pathologic review within 2 days of patient
registration on COG-D9902

- Newly diagnosed disease

- Metastatic disease (stage IV, clinical group IV)

- Has undergone initial surgical procedure (including biopsy) that provided the
definitive diagnosis within the past 42 days

- Parameningeal and paraspinal tumors allowed

- Patients with parameningeal (without intracranial extension [ICE]) and paraspinal
tumors should begin study chemotherapy at week 1 and radiotherapy at week 20

- Patients with evidence of ICE, as defined by contrast MRI showing that primary tumor
touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the
dura in contiguity to the primary site in brain or spinal cord, are eligible

- ICE is presumed to exist if the cerebrospinal fluid cytopathology is positive for
tumor at diagnosis

- Patients requiring emergency radiotherapy are eligible

- Patients requiring emergency radiotherapy (for intracranial extension or spinal
cord impingement) should begin study chemotherapy at week 1 (irinotecan
hydrochloride and vincristine) concurrently with radiation therapy

PATIENT CHARACTERISTICS:

- ECOG or Zubrod performance status (PS) 0-2 (Lansky PS 50-100% for patients < 10 years
of age and Karnofsky PS 50-100% for patients ≥ 10 years of age)

- Absolute neutrophil count ≥ 750/mm³*

- Platelet count ≥ 75,000/mm³*

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40
mL/min for infants < 1 year of age)

- Patients with urinary tract obstruction by tumor must meet the renal function criteria
listed above AND must have unimpeded urinary flow established via decompression of the
obstructed portion of the urinary tract

- SGPT < 2.5 times normal

- Bilirubin < 1.5 mg/dL

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by MUGA

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during study and for ≥ 1 month after
study completion

- No evidence of uncontrolled infection

- Able to undergo radiotherapy NOTE: *Abnormal blood counts allowed if there is bone
marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy except steroids

- No prior radiotherapy

- No concurrent aprepitant during ifosfamide or doxorubicin hydrochloride chemotherapy

- No concurrent dexrazoxane

- No concurrent sargramostim (GM-CSF) or pegfilgrastim