Medpedia

• Sarcoma

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
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
PRIOR CONCURRENT THERAPY:
Biologic therapy:
-  Not specified
Chemotherapy:
-  No prior chemotherapy
Endocrine therapy:
-  Prior steroids allowed
Radiotherapy:
-  No prior radiotherapy
Surgery:
-  See Disease Characteristics

OBJECTIVES:

-  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.

-  Compare the acute and late effects of these two treatment regimens in these patients.

-  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.

-  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.

-  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.

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.

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

• Biological: dactinomycin
• Biological: filgrastim
• Biological: sargramostim
• Drug: cyclophosphamide
• Drug: topotecan hydrochloride
• Drug: vincristine sulfate
• Procedure: surgical procedure
• Radiation: radiation therapy

• 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
  Safety Issue: No
• Failure-free survival (FFS) at end of therapy & at 3, 5, and 10 yrs after completion of therapy
  Safety Issue: No
• Survival at end of therapy & at 3, 5, and 10 yrs after completion of therapy
  Safety Issue: No
• Acute and late effects (e.g., sterility, second malignancy, radiation effects, and growth effects) of these regimens continuously for up to 10 years
  Safety Issue: No
• 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
  Safety Issue: No
• 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
  Safety Issue: No
• Preoperative radiotherapy followed by second-look surgery indicated for patients who respond poorly to induction chemotherapy
  Safety Issue: No
• 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
  Safety Issue: No
• 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
  Safety Issue: No

• Carola A. S. Arndt, MD
  Study Chair, Mayo Clinic

• Swiss Pediatric Oncology Group Lausanne
  Lausanne, CH 1011, Switzerland
  Completed
• Swiss Pediatric Oncology Group Geneva
  Geneva, CH 1211, Switzerland
  Completed
• Swiss Pediatric Oncology Group Bern
  Bern, CH 3010, Switzerland
  Completed
• San Jorge Children's Hospital
  Santurce, 00912, Puerto Rico
  Completed
• Puerto Rico Cancer Center at University of Puerto Rico - Medical Sciences Campus
  San Juan, 00936-5067, Puerto Rico
  Completed
• Starship Children's Health
  Auckland, New Zealand
  Completed
• University Medical Center Groningen
  Groningen, 9700 RB, Netherlands
  Completed
• Saskatoon Cancer Centre
  Saskatoon, Saskatchewan, S7N 4H4, Canada
  Completed
• Allan Blair Cancer Centre at Pasqua Hospital
  Regina, Saskatchewan, S4T 7T1, Canada
  Completed
• Centre de Recherche du Centre Hospitalier de l'Universite Laval
  Sainte Foy, Quebec, GIV 4G2, Canada
  Completed
• Hopital Sainte Justine
  Montreal, Quebec, H3T 1C5, Canada
  Completed
• Montreal Children's Hospital at McGill University Health Center
  Montreal, Quebec, H3G 1A4, Canada
  Completed

• Children's Oncology Group
  Lead Sponsor
• United States: Federal Government

• Petricoin EF 3rd, Espina V, Araujo RP, Midura B, Yeung C, Wan X, Eichler GS, Johann DJ Jr, Qualman S, Tsokos M, Krishnan K, Helman LJ, Liotta LA. Phosphoprotein pathway mapping: akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res. 2007 Apr 1;67(7):3431-40.

• Clinical trial summary from the National Cancer Institute's PDQ® database
  http://cancer.gov/clinicaltrials/COG-D9803